Incidence Of Atrial Fibrillation Research Articles

β-Hydroxybutyrate and Citrate Synthase as Potential Diagnostic Biomarkers in Aging-Related Atrial Fibrillation.

The incidence of atrial fibrillation (AF) increases with age; however, the precise mechanisms by which aging elevates AF risk and the effective biomarkers for managing AF in elderly patients remain unclear. We analyzed plasma samples from 100 elderly AF patients, 100 young and 100 elderly patients without atrial fibrillation (NAF), along with left atrial tissues obtained from both AF and NAF patients following valve replacement. Our findings indicate reduced levels of β-OHB and citrate synthase (CS) activity in elderly AF patients compared to their NAF counterparts. Statistical analysis revealed a protective association between β-OHB and CS activity concerning the occurrence of elderly AF. Furthermore, atrial tissues from elderly AF patients exhibited mitochondrial dysfunction, structural remodeling, and low-voltage areas. These results suggest that dysregulation of β-OHB levels and CS activity may contribute to aging-related AF by affecting mitochondrial function and atrial remodeling, highlighting their potential as diagnostic biomarkers for this condition.

Protein Biomarkers of Adverse Clinical Features and Events in Sarcomeric Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition that can lead to atrial fibrillation, heart failure, and sudden cardiac death in many individuals but mild clinical impact in others. The mechanisms underlying this phenotypic heterogeneity are not well defined. The aim of this study was to use plasma proteomic profiling to help illuminate biomarkers that reflect or inform the heterogeneity observed in HCM. The Olink antibody-based proteomic platform was used to measure plasma proteins in patients with genotype positive (sarcomeric) HCM participating in the HCM Registry. We assessed associations between plasma protein levels with clinical features, cardiac magnetic resonance imaging metrics, and the development of atrial fibrillation. We measured 275 proteins in 701 patients with sarcomeric HCM. There were associations between late gadolinium enhancement with proteins reflecting neurohormonal activation (NT-proBNP [N-terminal pro-B-type natriuretic peptide] and ACE2 [angiotensin-converting enzyme 2]). Metrics of left ventricular remodeling had novel associations with proteins involved in vascular development and homeostasis (vascular endothelial growth factor-D and TM [thrombomodulin]). Assessing clinical features, the European Society of Cardiology sudden cardiac death risk score was inversely associated with SCF (stem cell factor). Incident atrial fibrillation was associated with mediators of inflammation and fibrosis (MMP2 [matrix metalloproteinase 2] and SPON1 [spondin 1]). Proteomic profiling of sarcomeric HCM identified biomarkers associated with adverse imaging and clinical phenotypes. These circulating proteins are part of both established pathways, including neurohormonal activation and fibrosis, and less familiar pathways, including endothelial function and inflammatory proteins less well characterized in HCM. These findings highlight the value of plasma profiling to identify biomarkers of risk and to gain further insights into the pathophysiology of HCM.

Multimodal Data Integration to Predict Atrial Fibrillation

Abstract Background Many studies have utilized data sources such as clinical variables, polygenic risk scores, ECG, and plasma proteins to predict the risk of atrial fibrillation (AF). However, few studies have integrated all four sources from a single study to comprehensively assess AF prediction. Methods We included 8374 (Visit 3, 1993-1995) and 3,730 (Visit 5, 2011-2013) participants from the Atherosclerosis Risk in Communities Study to predict incident AF and prevalent (but covert) AF. We constructed a 1) clinical risk score using CHARGE-AF clinical variables, 2) polygenic risk score using pre-determined weights, 3) protein risk score using penalized and regularized logistic regression, and 4) ECG risk score from convolutional neural network. Risk prediction performance was measured using regularized logistic regression. Results After a median follow up of 15.1 years, 1910 AF events occurred since Visit 3 and 229 participants had prevalent AF at Visit 5. The AUC improved from 0.660 to 0.752 (95% CI, 0.741-0.763) and from 0.737 to 0.854 (95% CI, 0.828-0.880) after addition of polygenic risk score to the CHARGE-AF clinical variables for predicting incident and prevalent AF, respectively. Further addition of ECG and protein risk scores improved the AUC to 0.763 (95% CI, 0.753-0.772) and 0.875 (95% CI, 0.851-0.899) for predicting incident and prevalent AF, respectively. Conclusions A combination of clinical and polygenic risk scores was the most effective and parsimonious approach to predicting AF. Further addition of an ECG risk score or protein risk score provided only modest incremental improvement for predicting AF.

Residential exposure to transportation noise and risk of incident atrial fibrillation: a pooled study of 11 prospective Nordic cohorts

Transportation noise has been linked with cardiometabolic outcomes, yet whether it is a risk factor for atrial fibrillation (AF) remains inconclusive. We aimed to assess whether transportation noise was associated with AF in a large, pooled Nordic cohort. We pooled data from 11 Nordic cohorts, totaling 161,115 participants. Based on address history from five years before baseline until end of follow-up, road, railway, and aircraft noise was estimated at a residential level. Incident AF was ascertained via linkage to nationwide patient registries. Cox proportional hazards models were utilized to estimate associations between running 5-year time-weighted mean transportation noise (Lden) and AF after adjusting for sociodemographics, lifestyle, and air pollution. We identified 18,939 incident AF cases over a median follow-up of 19.6 years. Road traffic noise was associated with AF, with a hazard ratio (HR) and 95% confidence interval (CI) of 1.02 (1.00-1.04) per 10-dB of 5-year mean time-weighted exposure, which changed to 1.03 (1.01-1.06) when implementing a 53-dB cut-off. In effect modification analyses, the association for road traffic noise and AF appeared strongest in women and overweight and obese participants. Compared to exposures ≤40dB, aircraft noise of 40.1-50 and>50dB were associated with HRs of 1.04 (0.93-1.16) and 1.12 (0.98-1.27), respectively. Railway noise was not associated with AF. We found a HR of 1.19 (1.02-1.40) among people exposed to noise from road (≥45dB), railway (>40dB), and aircraft (>40dB) combined. Road traffic noise, and possibly aircraft noise, may be associated with elevated risk of AF. NordForsk.

Resting Heart Rate and Incident Atrial Fibrillation in Black Adults in the Jackson Heart Study

Resting heart rate (RHR) is a widely available measure of cardiovascular fitness that has been associated with several cardiovascular outcomes. RHR has previously been associated with the risk of atrial fibrillation (AF) among individuals of European ancestry, but little is known about this association in Black adults. To evaluate the association between RHR and incident AF in a large community-based sample of Black adults, independently of established risk factors. This cohort study uses data from the Jackson Heart Study, a prospective community-based cohort in Jackson, Mississippi. Participants without prevalent AF were included and were monitored for new-onset AF during follow-up, from 2000 through 2016. Data analysis was performed from August 1 to December 11, 2023. RHR was assessed from resting 12-lead electrocardiograms performed at examination 1 (2000-2004) and examination 3 (2009-2013). AF was identified from study electrocardiograms, hospitalization discharge diagnosis codes, and Medicare claims diagnosis codes. Cox regression was used to evaluate the association between baseline (examination 1) RHR and incident AF, adjusting for established AF risk factors. Among 4965 Black adults eligible for analysis, the mean (SD) age was 55 (13) years, 1830 (37%) were male, and the mean (SD) RHR at baseline was 65 (11) beats per minute (bpm). During a median (IQR) 14 (12-15) years of follow-up, there were 458 incident AF events, resulting in an incident rate of 7.5 per 1000 person-years (95% CI, 6.8-8.2 incidents per 1000 person-years). Each 10-bpm higher RHR was associated with a 9% higher risk of incident AF after adjustment for AF risk factors (hazard ratio, 1.09; 95% CI, 1.00-1.19). In a sensitivity analysis that excluded individuals with prior heart failure, prior myocardial infarction, and antiarrhythmic medication use at baseline, the hazard ratio was 1.14 (95% CI, 1.02-1.28). There was little evidence of effect modification of these associations by age, sex, body mass index, hypertension, or physical activity level. In this large prospective cohort study of Black adults, elevated baseline RHR was associated with increased risk of incident AF, consistent with findings from previous studies of European ancestry populations. Future research should focus on determining whether RHR can be used to screen patients at high risk of AF.

Incidence and outcomes of transient new-onset atrial fibrillation complicating acute coronary syndromes: results from a systematic review and meta-analysis

Abstract Background The overall risk of long-term adverse events of a transient episode of new-onset atrial fibrillation (AF) in patients with acute coronary syndrome (ACS) remains uncertain. This meta-analysis aimed to assess the prognostic impact of transient new-onset AF complicating ACS. Methods and results Cohort studies examining the risk of adverse events in patients with transient new-onset AF compared to those in sinus rhythm after ACS were identified through a comprehensive search of MEDLINE, Scopus, Cochrane, and Google Scholar Library. Studies reporting the incidence of ischaemic stroke events, recurrent AF, or all-cause mortality at the longest follow-up were included. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CI) were synthesized using inverse variance-weighted random-effects meta-analysis. In the seven observational studies included, comprising 151 735 patients, 6 597 (4.3%) experienced transient new-onset AF, which was associated with an increased risk of ischaemic stroke, recurrent AF, or all-cause mortality (HR: 2.24, 95% CI: 1.75–2.85; P < 0.0001; I2 = 30.76%; seven studies). The results remained consistent across each individual endpoint, including ischaemic stroke (HR 2.38, 95% CI: 1.64–3.44; P < 0.01; I2 = 50.2%; five studies), recurrent AF (HR 4.68, 95% CI: 2.07–10.59; P = 0.0002; I2 = 50.2%; four studies), and all-cause mortality (HR 1.36, 95% CI: 1.08–1.71; P = 0.0089; I2 = 53.25%; four studies). Meta-regression analyses revealed a significant increase in these adverse events associated with ST-elevation myocardial infarction (P = 0.001), while there was a tendency for their decrease associated with oral anticoagulant prescription at discharge (P = 0.07). Conclusions The occurrence of transient new-onset AF is associated with an elevated long-term risk of stroke, recurrent AF, and all-cause mortality in patients with ACS. Consequently, these data urge randomized clinical trials to assess the best antithrombotic regimen while potentially helping the current treatment decision-making process for these patients.

Editorial on incidence and outcomes of transient new onset atrial fibrillation complicating acute coronary syndromes: results from a systematic review and meta-analysis.

Editorial on incidence and outcomes of transient new onset atrial fibrillation complicating acute coronary syndromes: results from a systematic review and meta-analysis.

Atrial fibrillation detection on implantable loop recorders in embolic stroke of undetermined source

Abstract Introduction Embolic stroke of undetermined source (ESUS) represents 17% of all ischaemic strokes, and has a 5% annual stroke recurrence risk. Recent large randomised control trials failed to demonstrate a benefit of empirical anticoagulation for all ESUS patients, with sub-analyses supporting the need for a tailored approach to those patients at greatest risk of atrial fibrillation (AF) development. Understanding how the increased incidence of ILR-detected AF in the ESUS cohort, compares with ILR-detected AF in other cohorts is an essential step in understanding the significance of this finding. Purpose To compare the incidence of ILR-detected AF following ESUS against patients undergoing ILR implantation for non-stroke indications for example syncope and palpitations. Methods We retrospectively studied all patients without known AF who were referred to our institution for ILR implantation following ESUS, syncope or palpitations from 2009 to 2019. The primary endpoint was any detection of AF or atrial flutter (AFL) by ILR. Kaplan-Meier and multivariable Cox-regression analyses were utilised to account for time-to-event. Results A total of 750 patients were included and followed up for a mean of 731 days (SD 443). An ILR was implanted following ESUS in 323 patients and for another reason in 427 patients (figure 1). The incidence of AF was significantly higher among patients with ESUS compared to the non-ESUS group; 48.6% versus 13.8% (for any duration of AF) and 32.2% versus 12.4% (for AF lasting > 30 seconds) both p <0.001. Kaplan-Meier analysis (figure 2), showed significantly higher incidence of AF for ESUS for any duration of AF. This was driven predominantly by AF duration <6 minutes and between 5.5 hours and 24 hours. Importantly, in a multivariable Cox regression analysis, ESUS independently conferred an almost 5-fold increase in the hazard for any duration of AF (Hazard Ratio 4.948, 95% confidence interval 3.587 – 6.825, p<0.001). Conclusion The incidence of AF is significantly higher amongst ESUS versus non-ESUS patients monitored constantly by an ILR. A high number of ESUS survivors have short duration AF episodes. Further work is needed to determine the optimal treatment strategy of these AF episodes in ESUS considering AF duration and overall burden.

The incidence of atrial fibrillation in patients with interatrial shunt: is it reduced after surgical or transcatheter closure of the shunt?

Abstract Background Atrial fibrillation (AF) is a prevalent diagnosis among individuals with interatrial shunts, and the prevalence increases with age (1). Since the 1990s, interventionists have introduced transcatheter techniques, to close interatrial shunts, while surgical procedures reserved in cases of technical complexity (2). Despite the potential reduction in AF incidence post interatrial shunt closure, discernible modifications in the cardiac conduction system may persist (3). Notwithstanding, reports indicate an incidence of new-onset AF in approximately 10-25% of patients after interatrial shunt closure, with a pronounced prevalence among elderly (4). This study aims to delineate the incidence of AF subsequent to interatrial shunt, surgical och transcatheter, closure within a national cohort in Sweden. Methods The study includes all patients diagnosed with an interatrial shunt, atrial septal defect and patent foramen ovale, classified using the International Classification of Diseases, 10th edition (ICD-10), as documented in the Swedish National Patient Register, along with data sourced from the Cause of Death Register. Patients with multiple diagnoses of other congenital heart diseases are excluded, and interventions performed between 1997 and 2017 are identified using the NOMESCO surgical classification. Comorbidities such as chronic ischemic heart disease, myocardial infarction, heart failure, hypertension, and diabetes are considered, with the primary endpoint being the incidence of AF post-intervention. Results A total of 3,426 patients with interatrial shunts underwent intervention between 1997 and 2017, with a mean follow-up duration of 6.2 years. Among these, 49% (n=1,725) underwent transcatheter closure, while 41 patients underwent both transcatheter and surgical procedures. The mean age was 36 years, with 9% presenting with heart failure at baseline. Before the intervention, 14% (n=483) had AF, increasing to 22% (n=755) post-intervention. Of those developing AF post-intervention, 16% (n=119) experienced the AF event within 60 days, evenly distributed between transcatheter and surgical procedures. Over 40% of patients with post-intervention AF had an average age of 62. The incidence of AF post-intervention was 1.6 per 100 patient-years (see Figure). Stroke incidence was 3.6 per 100 patient-years and the mortality rate was 7% (n=257) during follow up (see Table). Conclusions Patients with interatrial shunts exhibit a high incidence of AF, which further escalates following closure of the interatrial shunt, not only within the first few days post-intervention, particularly among the elderly population. This can relate to high incidence of ischemic stroke.Figure

Associations between biomarkers and P-wave indices in patients with heart failure

Abstract Background Atrial structural abnormalities linked to the risk of atrial fibrillation (AF), as indicated by P-wave indices on surface ECG, are associated with the fibrotic transformation of the atrial myocardium. To what extent incident AF can be predicted by ECG characteristics in patients with advanced atrial structural remodeling, such as patients with heart failure (HF), is less well studied. Purpose To evaluate the association between P-wave indices and biomarkers implicated in cardiac fibrosis, and incident AF in patients with HF. Methods Patients with new-onset or worsening of HF were prospectively recruited in a observational study (n=501) and followed-up for 5 years. Blood samples were collected for analysis using proximity extension assay that included a subset of biomarkers that were associated with fibrosis development (TIMP-2, MMP-2, MMP-3, MMP-9, ST-2, GDF-15, Gal-3). All ECGs ever recorded in the hospital catchment area were exported in digital format and processed using Glasgow algorithm for calculation of the P-wave indices (P-wave duration [PWD], P-wave terminal force in V1 [PTFV1] and P-wave axis [Paxis]) and rhythm identification. AF diagnosis was ascertained by manual ECG review. Only patients who did not have AF reported or ECG documented at enrolment were included in the analysis. Of those subjects, 121 patients also had biomarkers of fibrosis analyzed. Cox-regression analyses were used to assess biomarkers’ and p-wave indices’ associations with incident AF. Results After exclusion of patients with prevalent AF (n=317), 184 patients comprised the study group (mean age of 71 years, 33.2% women, 121 patients with biomarker data available). During follow-up, incident AF was observed in 39 patients. At enrolment, PWD>120 ms was observed in 38.7%, abnormal PTFV1>40 mm*ms in 24.5% and Paxis<0° in 5.4%. Among the seven biomarkers assessed, five demonstrated significant associations with incident AF in adjusted analyses: TIMP4 (HR 1.78; 95%CI 1.03-3.05; p=0.037); MMP2 (HR 1.97; 95%CI 1.03-3.80; p=0.042), MMP3 (HR 1.39; 95%CI 1.03-1.88; p=0.031); ST2 (HR 1.91; 95%CI 1.29-2.83; p=0.001) and GDF-15 (HR 2.56; 95%CI 1.50-4.35; p=0.001) (Figure 1). However, none of the tested P-wave variables (P-wave duration, P-wave terminal force, and P-wave axis) were associated to incident AF. Conclusions In this prospective long-term follow-up study of patients admitted for acute HF, biomarkers with proven associations to fibrosis were strongly associated with incident AF. P-wave indices used for prediction of AF in epidemiological cohorts appear to have limited value in patients with HF who have high prevalence of ECG atrial abnormalities at baseline.

Incidence of atrial fibrillation detected by an insertable cardiac monitor in a large real-world cohort of heart failure patients with reduced and preserved ejection fraction

Abstract Background Subcutaneous implantable cardiac monitors (ICM) have the capability to detect atrial fibrillation (AF) episodes with high degree of accuracy [1]. Objective We investigated the incidence of AF in patients implanted with an ICM and a clinical history of heart failure (HF) with reduced or preserved left ventricular ejection fraction (LVEF). Methods Patients with history of HF admissions who were implanted with an ICM were identified from the aggregated and de-identified electronic health record (EHR) database during 2007-2021. The device collected data were merged with the EHR data to create a de-identified database of real-world patients. Patients were included if they had ≥180 days of device follow-up. ICMs detect AF based on incoherence of RR intervals and absence of single p-wave between two R-waves [1]. All ICM detected AF episodes stored with at least 30 seconds of ECG at onset were adjudicated using an artificial intelligence (AI) model. The AI model was previously trained and validated using over 60K manually adjudicated episodes and was shown to have an accuracy of over 97% [2]. ICM detected AF episodes with AI model based true probability of AF ≥ 0.9 was analyzed. The Kaplan-Meier incidence curves for AF incidence as a function of episode duration, clinical history of AF, and LVEF are reported. Results A total of 1020 LINQ ICM patients with history of HF admission prior to implant were identified from the deidentified real-world dataset. LVEF was available in 889 (87%) patients, of whom 394 (44%) had EF <50%, and 495 (56%) had EF≥50%. NYHA class was available in 296 (29%) patients, of whom 39 (13%) were class I, 126 (43%) were class II, 112 (38%) were class III, and 19 (6%) were class IV. Patients had an average age of 68±13 years with 52% being males and had clinical history of hypertension in 95%, diabetes in 56%, coronary artery disease in 75%, AF in 57%, stroke/TIA in 51%, and renal dysfunction in 53%. A total of 911 patients with ≥180 days of follow-up (average follow-up of 25.8 months) were included. A total of 8407 episodes from 358 patients were classified by the AI model as true AF. The incidence of AF as a function of episode duration, clinical history of AF and reduced vs preserved LVEF are shown in Figures A, B, and C respectively. Incidence of AF, as detected by an ICM over 42 months of follow-up, was estimated to be 38% to 46% depending on AF episode duration. Estimated 42-month AF incidence was 23% in patients with no clinical history of AF. The 42-month AF incidence was 44% vs 47% in HF patients with reduced versus preserved LVEF. Conclusion Incidence of AF, as detected by an ICM over 3 years of follow-up, was estimated to be in close to half of ICM patients with history of HF events. Close to one fourth of the patients with no prior clinical history of AF had newly detected AF. AF incidence was similar in HF patients with preserved versus reduced LVEF in this real-world cohort.

Orthostatic blood pressure changes and incident atrial fibrillation in patients with hypertension: Insights from the SPRINT trial

Abstract Background Exaggerated orthostatic changes in systolic blood pressure (SBP) were associated with adverse cardiovascular events. However, the predictive role of SBP hyperactivity to standing on incident atrial fibrillation (AF) is unclear. Purpose We aim to assess the association between orthostatic SBP changes and incident AF. Methods We performed a post hoc analysis of SPRINT (Systolic Blood Pressure Intervention Trial), a randomized controlled trial comparing intensive (<120 mm Hg) and standard (<140 mm Hg) SBP interventions in participants with hypertension. Participants with standing SBP <110 mm Hg were not eligible for randomization according to the SPRINT protocol. Participants without AF who had seated and standing SBP measurements at baseline and available baseline or follow-up ECG were included in this analysis. Orthostatic SBP changes were defined as standing SBP minus seated SBP. Patients were grouped into tertiles of orthostatic SBP changes. AF was ascertained from the standard 12-lead ECG obtained at baseline, year 2, year 4, a close-out visit, and any visit when suspected of serious adverse events. We used Cox proportional regression models and restricted spline curves to assess the association of orthostatic SBP changes with incident AF. Results Among 8,455 participants included in this analysis, 327 incident AF cases occurred during follow-up. The restricted spline curve depicted a U-shaped relationship between orthostatic SBP changes and incident AF in the unadjusted model (P for nonlinearity = 0.012) (Figure 1). After adjusting for age, female, race, smoking, alcohol use, history of cardiovascular disease, history of chronic kidney disease, and body mass index, a SBP increase ≥ 6 mm Hg to standing was independently associated with a 43% higher risk of incident AF (HR: 1.43; 95% CI: 1.07-1.90; P = 0.014) compared to nonsignificant orthostatic SBP changes (>-4 mm Hg to <6 mm Hg). A SBP decrease ≥ 4 mm Hg to standing showed a nonsignificant higher risk of developing AF compared to SBP changes of >-4 mm Hg to <6 mm Hg (Figure 2). In subgroup analysis, the results presented a similar tendency to the main result. Sensitivity analyses also generated consistent results while additionally adjusting for seated and standing blood pressure or heart rate. Conclusion In this post hoc analysis of the SPRINT trial, exaggerated SBP increase to standing independently predicts incident AF.Figure 1Figure 2

Proteomic and genomic evaluation of plasma protein biomarkers for atrial fibrillation

Abstract Background Atrial fibrillation (AF) is a common arrhythmia and an important cause of ischemic stroke. Several plasma proteins have been suggested as biomarkers for the risk of AF and subsequent stroke in previous studies, but validation in independent cohorts is needed. Large-scale integration of proteomics with genetic and clinical data holds potential for refinement of disease prediction and risk stratification. Purpose This study aimed to evaluate previously suggested plasma protein biomarkers of AF and ischemic stroke using plasma protein measurements in a large cohort. Methods Ten tentative protein biomarkers previously associated with AF or ischemic stroke in AF patients, were evaluated in a nested case-control study comprising 49,757 individuals from the UK biobank (UKB). Plasma proteins were measured by normalized protein expression on the Olink platform. Outcomes were incident AF and ischemic stroke. The proteins were evaluated in Cox regression models adjusted for sex, age, and clinical risk factors. To assess whether the proteins were independent predictors, they were evaluated in sensitivity analyses with additional adjustment for NT-proBNP levels. Polygenic risk scores were calculated for plasma protein concentrations using the PRS-CS-auto algorithm and tested for association with AF or ischemic stroke in an independent subset of the UKB cohort without plasma protein measurements (n=379,392). Results All ten plasma proteins were associated with incident AF in the primary model, and eight were associated with incident ischemic stroke (P-values < 0.0025 for all). Adjusted for NT-proBNP levels, the proteins interleukin-6, GDF15, angiopoietin 2, and Troponin-I remained independently associated with AF, and the proteins GDF15, Cystatin-C, interleukin-6, ADAMTS13, and FGF23 remained independently associated with ischemic stroke. Polygenic risk scores for NT-proBNP and angiopoietin 2 were associated with increased rates of AF. No polygenic scores were significantly associated with ischemic stroke. Conclusion Large-scale proteomic evaluation validated ten plasma proteins associated AF and found eight to be associated with ischemic stroke. Seven proteins were associated with AF or ischemic stroke independently of NT-proBNP levels. Additional genomic evaluation provided evidence of associations between incident AF and genetically predicted plasma levels of angiopoietin 2 and NT-proBNP. As proteomic analyses of the plasma proteome become cheaper and more readily available, these findings could contribute to future risk stratification and selection of individuals for AF screening programs.Proteins associated with AFProteins associated with ischemic stroke

A comprehensive evaluation of available evidence of mavacamten in obstructive HCM: a meta-analysis of randomised controlled trials

Abstract Introduction Obstructive hypertrophic cardiomyopathy (HCM) poses a significant clinical challenge, characterized by left ventricular hypertrophy and impaired cardiac function. mavacamten, a novel medication targeting the sarcomere protein myosin, has emerged as a promising therapeutic option for patients with symptomatic obstructive HCM. Despite its potential efficacy, the comparative effectiveness and safety of Mavacamten remain uncertain, necessitating a comprehensive evaluation of available evidence. Purpose We aimed to give a comprehensive appraisal on mavacamten as a treatment option for patients with obstructive HCM informing clinical decision-making. Methods We systematically searched PubMed, Web of Science, Scopus, and Cochrane Central, and EMBASE from inception until February 2024. We included randomised controlled trials (RCTs) comparing mavacamten versus placebo in patients with obstructive HCM. The primary outcomes were improvement in NYHA class, Change from baseline in KCCQ-CSS, and the incidence of atrial fibrillation. All data were pooled as either Mean difference in the random effect model with the corresponding SD or pooled as RR and 95% CI for dichotomous data. Results Four randomised controlled trials involving 503 patients were included in the final analysis. the overall odds ratio demonstrated a substantial preference for Mavacamten in achieving more than a one-level improvement in NYHA functional class from baseline (OR: 3.83 (95% CI [2.54 to 5.77], P=0.0001). However, there was no significant difference in terms of KCCQ-CSS (MD= 1.06, 95% CI [ -0.03 to 2.15], P=0.06) or the incidence of atrial fibrillation (OR=1.27, 95% CI [0.51 to 3.14], P=0.60). Conclusion Mavacamten showed a significant improvement on NYHA functional class, with no observed significance in terms of reducing the incidence of AF, or improving the KCCQ-CSS score.KCCQ-CSSNYHA

Left atrial function for predicting atrial fibrillation: a machine learning approach

Abstract Background Common risk scores for atrial fibrillation (AF) are based on clinical risk factors, and little is known about the contribution of left atrial (LA) function parameters to risk assessment. Purpose To determine whether a machine learning-based model that includes LA function parameters outperforms a commonly used risk scores, the CHARGE-AF, in predicting AF. Methods Participants in the Atherosclerosis Risk in Communities (ARIC) Study (a community-based cohort study in the USA) who attended visit 5 (2011-2013) and without a history of AF were included in this analysis. Incident AF was ascertained from ECG during study visits, hospitalization discharge codes, and death certificates. Random survival forest methodology was used to build a prediction model for AF; candidate variables included traditional clinical risk factors and measures of LA structure and function. Dataset was randomly split into a training (75%) and testing (25%) cohort. For each variable, importance was measured based on the reduction in Harrell’s c-statistic if the variable was randomly permuted prior to obtaining predicted values. Variables significantly associated with AF were included in the final model. Model calibration was tested using the Greenwood-Nam-D'Agostino (GND) test. Discrimination ability of our model was assessed in the testing cohort using Harrell’s c-statistic and compared with that of the CHARGE-AF model. Results 4,909 participants (59% female, 22% Black, mean age 75 years) were included. During a median follow-up of 7.0 years (1st-3rd quartile: 5.4-7.8), 650 participants developed AF. Variables significantly associated with incident AF were race, triglycerides, systolic blood pressure, coronary heart disease, age, LA maximal volume index, NT-proBNP, and LA reservoir strain (Figure 1). LA reservoir strain was the variable most strongly associated with AF. The final model showed good discrimination (c-statistic (95% CI): 0.734 (0.698-0.768)). The GND test did not detect statistically significant miscalibration (GND p=0.08). Compared with our model, CHARGE-AF had lower discrimination ability (c-statistic (95% CI): 0.635 (0.594-0.677)) and the difference was statistically significant (difference in c-statistic (95% CI): 0.099 (0.043-0.152)). Conclusion A machine learning-based model with few variables including LA function outperforms a commonly used risk model in predicting AF. Incorporation of LA functional assessment may help inform clinicians regarding individual risk of AF.

Proteinuria and the risk of incident atrial fibrillation according to diabetes stage in patients with diabetes: a nationwide population-based cohort study

Abstract Background Proteinuria and diabetes mellitus (DM) are established cardiovascular risk factors, both independently associated with an increased risk of atrial fibrillation (AF). Despite previous findings correlating proteinuria amount with incident AF, regardless of DM diagnosis, the nuanced association at different stages of DM warrants further investigation. Purpose This study aimed to delve into and compare the relationship between proteinuria amount and the risk of incident AF in patients across various stages of DM. Methods A cohort of 3,866,428 individuals without prior AF and type 1 DM, who underwent the 2009 health checkup provided by the National Health Insurance Service in Korea, were categorized into five DM stages: normal, prediabetes, new-onset DM, early DM (diagnosed < 5 years), and late DM (diagnosed ≥ 5 years). Proteinuria was graded using the urine dipstick test, ranging from negative to 3+ or more. AF incidence was tracked until December 31, 2020. Results The cohort, with an average age of 47.0 ± 13.9 years and 45.4% females, demonstrated escalating annual AF incidence rates from 1.90 to 6.45 per 1000 person-years across DM stages (p<0.001) (Figure). Similarly, the rates increased from 2.28 to 7.28 per 1000 person-years by proteinuria levels (p<0.001) (Figure). Adjusted Cox regression models revealed a heightened risk of incident AF associated with higher proteinuria amounts in all DM stages (adjusted hazard ratios for urine dipstick 3+ or more: 1.57, 1.76, 1.44, 2.32, and 2.23, respectively). Notably, the association between proteinuria and incident AF was more pronounced in individuals with early and late DM compared to those with prediabetes and new-onset DM (Figure). Conclusions At each DM stage, from prediabetes to late DM, a higher level of proteinuria corresponds to an increased risk of AF development. Furthermore, a stronger association was observed in patients with longer DM duration compared to those with prediabetes or new-onset DM. These findings underscore the significance of monitoring proteinuria levels across DM stages to assess AF risk comprehensively.

Relationship of serum vitamin D levels with atrial fibrillation incidence: The HUNT Study

Abstract Background Evidence on the association between serum vitamin D levels and incidence of atrial fibrillation (AF) was inconclusive. To elucidate the nature of the association, we studied the relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and AF incidence in the Norwegian Trøndelag Health (HUNT) Study using both conventional observational and Mendelian Randomization (MR) approaches. Methods 3394 adult participants without AF diagnoses were followed up from HUNT3 (2006-2008) to 2021 in a prospective cohort. Average serum 25(OH)D levels over ten years between HUNT2 (1995-1997) and HUNT3 were calculated and categorized into <50 and ≥50 nmol/L as exposure. AF diagnoses were retrieved from hospital registers and validated by medical doctors. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Furthermore, a one-sample MR was conducted among 36,554 adults who participated in both HUNT2 and HUNT3. An externally weighted genetic risk score based on 19 vitamin D-related genetic variants, chosen for their clear biological functions in serum vitamin D transport, synthesis and metabolism, was used as instrument. We applied the Wald ratio method to assess the causal effect. Results During a median 13-year follow-up, 303 AF cases were diagnosed in the prospective cohort. Serum 25(OH)D level <50.0 nmol/L was associated with a 26% reduced incidence of AF (HR 0.74, 95% CI 0.58 to 0.95), compared to serum 25(OH)D ≥50 nmol/L after adjustment for confounders. Genetically determined 10 nmol/L decrease in serum 25(OH)D level was associated with a 7% reduced incidence of AF (HR 0.93, 95% CI 0.86 to 1.00) in the MR analysis. Sensitivity analyses supported this positive association. Conclusions We found a consistent positive association between serum 25(OH)D level and AF incidence in the Norwegian HUNT population using both observational and MR approaches. Key messages • Serum vitamin D levels appeared to be positively associated with the incidence of AF. • Vitamin D supplementation should be prescribed with caution, especially for people at high risk for AF.

Elevation of circulating FGF23 in chronic kidney disease promotes atrial fibrosis through the AKT pathway

Abstract Background The relationship between chronic kidney disease (CKD) and atrial fibrillation (AF) remains unclear. Elevated level of fibroblast growth factor 23 (FGF23) is highly associated with increased cardiovascular disease and mortality in patients suffering from CKD. In recent years, studies have shown that FGF23 promotes cardiac hypertrophy through FGFR4, suggesting that FGF23 may be an important bridge between the heart and kidney. Purpose In this study, we sought to use a well-established rat model of CKD to further characterize the effects of CKD on AF and to identify potential drivers of CKD-induced AF. Methods 14 SD rats were randomly selected to undergo 5/6 nephrectomy and fed for 15 weeks to establish a CKD model, while the SHAM group (8 rats) underwent the same surgery without removing kidney tissue. Body weight, blood pressure, renal function, cardiac ultrasound, epicardial electrocardiography, and pathological indices were monitored in both groups. Gene sequencing was performed on the left atria to search for differentially expressed genes. Rat atrial fibroblasts were selected for further mechanism exploration. We chose TGF-β to stimulate fibroblasts to mimic the process of fibrosis in vivo, and then administered FGFR inhibitors to explore the downstream molecular mechanisms. Results Systolic blood pressure and creatinine were elevated in the CKD group. Compared with the SHAM group, the incidence of AF was significantly higher, left atrial diameter was significantly larger, and epicardial electrical markers showed that left atrial electrical conduction velocity was significantly slower and conduction heterogeneity was significantly increased in the CKD group. Pathologic staining of the left atrium showed significant fibrosis in the CKD group. Consistent with previous findings, FGF23 was significantly elevated in CKD rats. Transcriptomic sequencing revealed that FGFR4 expression was significantly upregulated in the left atrium of CKD rats, The results in rat atrial fibroblasts showed that blocking FGFR4 expression inhibited TGF-β-induced fibrosis and was mediated by the AKT pathway. Conclusions The mechanism of CKD-induced AF is that CKD promotes both structural and electrical remodeling of the atria. Further investigation of its possible downstream molecules revealed that elevated FGF23 in the CKD circulation promotes the development of atrial fibrosis by binding to FGFR4 through the AKT pathway.

Polygenic risk score for prediction of atrial fibrillation according to presence of the hypertrophic cardiomyopathy

Abstract Background The significance of genetic predisposition in predicting atrial fibrillation (AF) is well recognized, yet its role in hypertrophic cardiomyopathy (HCM) patients remains less clear. Objective In this study, we aimed to elucidate the impact of genetic risk on the development of AF in both HCM and non-HCM patients. Methods This retrospective analysis examined 1,180 HCM patients (mean age 61.1±7.1, 63.0% male) and 476,238 non-HCM patients (mean age 57.0±8.1, 45.3% male) from the UK Biobank. Participants were stratified based on their validated polygenic risk score (PRS) for AF: the bottom 10% constituted the low genetic risk group, the top 10% comprised the high genetic risk group, and the remainder fell into the intermediate genetic risk group. We assessed the incidence of AF and major cardiovascular events and analyzed predictors, including genetic risk. Results Among HCM patients, no significant differences in baseline characteristics were observed based on genetic risk, except for the rate of CIED implantation (P=0.036). Conversely, among non-HCM patients, variations in age, gender, and comorbidities were noted according to genetic risk. The HCM patients were categorized into three groups based on risk, with respective AF incidence rates of 2.4, 3.6, and 5.4 events per 100 person-years, respectively. In non-HCM patients, the incidence of AF per 100 person-years was 0.2, 0.5, and 1.0, respectively. Genetic risk emerged as a significant predictor of AF in both HCM and non-HCM patients, although with a higher hazard ratio observed in non-HCM patient (HR, 2.51; 95% CI, 1.59–3.98 vs. HR, 4.77; 95% CI, 4.47–5.09) (P=0.003 for interaction). In non-HCM patients, predictors of AF included age, male sex, body mass index, smoking history, and a history of hypertension, diabetes, heart failure, stroke, and myocardial infarction, in addition to PRS. However, in HCM patients, only age, diabetes, and a history of stroke were identified as independent predictors of AF. Moreover, high genetic risk was significantly associated with the risk of major adverse cardiovascular events. Conclusions In conclusion, our study indicates associations between genetic predisposition and AF occurrence in both HCM and non-HCM patients.

A matter of inflammation: CAR T-cell therapy and atrial fibrillation

Abstract Background Chimeric antigen receptor (CAR) T-cell therapy has been revolutionary in the treatment of blood cancers, but has been associated with arrhythmias such as atrial fibrillation (AF). Whether the incidence of AF has changed over time and if contributing risk factors are present remains to be defined. Methods Leveraging the Mayo Electronic Medical Record, we extracted a cohort of patients who underwent CAR T-cell therapy between 2016 and 2022. From this cohort, we identified those who had a diagnosis of AF at any point. We then defined the endpoint of interest as the first episode of new or recurrent AF during or after CAR T-cell infusion. Fine and Gray subdistribution hazard modeling was used to calculate the association of patient characteristics to the endpoint of interest. Variables with P<0.20 in univariate modeling were chosen for the multivariate model. Significance was defined as P<0.05. Results There were 328 patients who underwent CAR T-cell therapy between 2016 and 2022. Of this cohort, 27 (8.2%) patients had a pre-existing diagnosis of AF, of which 6 had recurrence of AF after CAR T (22.2%), while 21 (77.8%) did not. Of the 301 patients without a prior history of AF, 8 (2.7%) patients developed new-onset AF after CAR T. The majority of the 14 new or recurrent AF events (4.3% overall incidence) occurred within 30 days of receiving CAR T (N=10, 71.4%), the remainder after 180 days (Figure 1). No trend in declining incidence over time was noted. Prior AF, neurotoxicity, and inflammation (cytokine release syndrome and macrophage activating syndrome-like (MAS-L)) were strongly associated with the risk of developing new or recurrent AF (Table 1). Only presence of MAS-L remained an independent predictor in the multivariate model (HR 15.4, 95% CI 3.9-61.2, P<0.001). Conclusion AF is mainly seen early following CAR T-cell therapy, and mainly in association with severe inflammatory responses. Early and aggressive treatment of CRS and MAS-L may be recommendable for patients undergoing CAR-T therapy, especially for those with a prior history of AF.