Risk Of Atrial Fibrillation Research Articles

Association of central arterial stiffness with atrial myopathy: the Atherosclerosis Risk in Communities (ARIC) study.

Atrial myopathy-defined as abnormal left atrial (LA) size and function-is associated with an increased risk of atrial fibrillation, heart failure, and dementia. Central arterial stiffness is associated with increased atrial afterload and fibrosis and may be a risk factor for atrial myopathy. We examined the association of carotid-femoral pulse wave velocity (cfPWV) with LA function and assessed potential causal relationships. We included 2825 Atherosclerosis Risk in Communities (ARIC) study participants from Visit 5 (2011-2013). cfPWV was related to echocardiographic LA function continuously per 1-SD and categorically in quartiles. Mendelian randomization (MR) analysis was performed using U.K. Biobank-derived genetic variants associated with arterial stiffness index and cardiac magnetic resonance measures of LA function. When analyzed per SD increment (297.6 cm/s), higher cfPWV was significantly associated with lower LA reservoir and conduit strain (β = -0.53%, 95% CI [-0.81, -0.25] and β = -0.46%, 95% CI [-0.68, -0.25], respectively) after adjusting for demographics, clinical characteristics, systolic blood pressure, and left ventricular (LV) morphology and function. In MR analyses there was a non-significant inverse association of arterial stiffness index with LA total, passive, and active emptying fractions. Higher cfPWV is associated with lower LA reservoir and conduit strain, independent of systolic blood pressure and LV morphology and function. No evidence for a causal relationship between arterial stiffness index and alterations in LA function was found. Future studies should examine the prospective association of central arterial stiffness with LA function alterations.

Comprehensive mendelian randomization reveals atrial fibrillation-breast cancer relationship and explores common druggable targets.

Atrial fibrillation (AF) and breast cancer pose significant risks to human health. The reasons behind the concurrent occurrence of AF and breast cancer remain unclear, leading to complex treatment approaches. Mendelian Randomization (MR) analyses aim to offer genetic evidence supporting the causation of AF and breast cancer and to investigate common druggable genes associated with both conditions. We used two-samples of MR to sequentially explore the causal relationship between atrial fibrillation and breast cancer, and between atrial fibrillation and breast cancer therapeutic drugs, and verified the stability of the results through colocalization analysis. We utilized the Connectivity map database to infer the direction of drug effects on disease. Finally, we explored druggable genes that play a role in AF and breast cancer and performed a Phenome-wide MR analysis to analyze the potential side effects of drug targets. We found 15 breast cancer therapeutic drugs that significantly support a causal association between AF and breast cancer through expression in blood and/or atrial appendage tissue. Among these, activation of ANXA5 by Docetaxel, inhibition of EIF5A by Fulvestrant, and inhibition of GNA12 by Tamoxifen increased the risk of AF, while inhibition of ANXA5 by Gemcitabine and Vinorebine and inhibition of PCGF6 by Paclitaxel reduced the risk of AF. Inhibition of MSH6 and SF3B1 by Cyclophosphamide, as well as inhibition of SMAD4 and PSMD2 and activation of ASAH1 and MLST8 by Doxorubicin can have bidirectional effects on AF occurrence. XBP1 can be used as a common druggable gene for AF and breast cancer, and there are no potential side effects of treatment against this target. This study did not find a direct disease causality between AF and breast cancer but identified 40 target genes for 15 breast cancer therapeutic drugs associated with AF, clarified the direction of action of 8 breast cancer therapeutic drugs on AF, and finally identified one common druggable target for AF and breast cancer.

Childhood Adiposity and Risk of Major Clinical Heart Diseases in Adulthood: A Mendelian Randomization Study.

The causal relationship between childhood adiposity and adult risk of heart diseases has not been clearly demonstrated. This study aims to ascertain whether genetically predicted childhood body mass index (BMI) and childhood obesity are causally associated with adult coronary heart disease, myocardial infarction, heart failure, atrial fibrillation, hypertrophic cardiomyopathy, and pulmonary heart disease. To investigate the causative relationships and underlying mechanisms between childhood adiposity and adult heart diseases, 3 main methods of Mendelian randomization were used: 2-sample Mendelian randomization, multivariable Mendelian randomization with controlling for several cardiometabolic risk variables, and mediation analysis. Every 1-SD rise in genetically predicted childhood body mass index was associated with 24% (odds ratio [OR], 1.24 [95% CI, 1.12-1.37]), 28% (OR, 1.28 [95% CI, 1.14-1.42]), 28% (OR, 1.28 [95% CI, 1.14-1.42]), and 27% (OR, 1.27 [95% CI, 1.04-1.49]) higher risk of coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation, respectively. Every 1-unit increase in log-odds in childhood obesity was associated with 11% (OR, 1.11 [95% CI, 1.06-1.16]), 14% (OR, 1.14 [95% CI, 1.04-1.23]), 10% (OR, 1.10 [95% CI, 1.03-1.18]), and 20% (OR, 1.20 [95% CI, 1.08-1.32]) higher risk of coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation, respectively. The link between childhood adiposity and adult heart diseases was found to be mediated by high-density lipoprotein cholesterol, triglyceride, hypertension, and type 2 diabetes. Our findings support the causal relationships between childhood adiposity and risk of adult coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation. Blood lipids, hypertension, and type 2 diabetes are factors that mediate the aforementioned associations.

Omega-3 Fatty Acids and Arrhythmias.

The pro- and antiarrhythmic effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been extensively studied in preclinical and human trials. Despite early evidence of an antiarrhythmic role of n-3 PUFA in the prevention of sudden cardiac death and postoperative and persistent atrial fibrillation (AF), subsequent well-designed randomized trials have largely not shown an antiarrhythmic benefit. Two trials that tested moderate and high-dose n-3 PUFA demonstrated a reduction in sudden cardiac death, but these findings have not been widely replicated, and the potential of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to reduce arrhythmic death in combination, or as monotherapy, remains uncertain. The accumulated clinical evidence does not support supplementation of n-3 PUFA for postoperative AF or secondary prevention of AF. Several large, contemporary, randomized controlled trials of high-dose n-3 PUFA for primary or secondary cardiovascular prevention have demonstrated a small, significant, dose-dependent increased risk of incident AF compared with mineral oil or corn oil comparator. These findings were reproduced with both icosapent ethyl monotherapy and a mixed EPA+DHA formulation. The proarrhythmic mechanism of increased AF in contemporary cohorts exposed to high-dose n-3 PUFA is unknown. EPA and DHA and their metabolites have pleiotropic cardiometabolic and pro- and antiarrhythmic effects, including modification of the lipid raft microenvironment; alteration of cell membrane structure and fluidity; modulation of sodium, potassium, and calcium currents; and regulation of gene transcription, cell proliferation, and inflammation. Further characterization of the complex association between EPA, EPA+DHA, and DHA and AF is needed. Which formulations, dose ranges, and patient subgroups are at highest risk, remain unclear.

Sex Differences in Profile and In-Hospital Death for Acute Stroke in Chile: Data From a Nationwide Hospital Registry.

Knowledge of local contextual sex differences in the profile and outcome for stroke can improve service delivery. We aimed to determine sex differences in the profile of patients with acute stroke and their associations with in-hospital death in the national hospital database of Chile. We present a retrospective cohort based on the analysis of the 2019 Chilean database of Diagnosis-Related Groups, which represents 70% of the operational expenditure of the public health system. Random-effects multiple logistic regression models were used to determine independent associations of acute stroke (defined by main diagnosis International Classification of Diseases, Tenth Revision [ICD-10] codes) and in-hospital death, and reported with odds ratios (ORs) and 95% CIs. Of 1 048 575 hospital discharges, 15 535 were for patients with acute stroke (7074 [45.5%] in women), and 2438 (15.6%) of them died during hospitalization. Differences by sex in sociodemographic and clinical characteristics were identified for stroke and main subtypes. After fully adjusted model, women with ischemic stroke had lower in-hospital death (OR, 0.79 [95% CI, 0.69-0.91]) compared with men; other independent predictors included age per year increase (OR, 1.03 [95% CI, 1.03-1.04]), chronic kidney disease (OR, 1.47 [95% CI, 1.20-1.80]), atrial fibrillation (OR, 1.50 [95% CI, 1.26-1.80]), and other risk factors. Conversely, for intracerebral hemorrhage, women had a higher in-hospital mortality rate than men (OR, 1.19 [95% CI, 1.02-1.40]); other independent predictors included age per year increase (OR, 1.009 [95% CI, 1.003-1.01]), chronic kidney disease (OR, 1.55 [95% CI, 1.23-1.97]), oral anticoagulant use (OR, 1.88 [95% CI, 1.37-2.58]), and other risk factors. Sex differences in characteristics and in-hospital death of hospitalized patients exist for acute stroke in Chile. In-hospital death is higher for acute ischemic stroke in men and higher for intracerebral hemorrhage in women. Future research is needed to better identify contributing factors.

Abstract Or117: JNK2-mediated gut-heart crosstalk in aging-associated AF pathogenesis.

Introduction: Aging is an independent risk factor for atrial fibrillation (AF). We recently revealed a critical role of activated cardiac stress kinase JNK2 in AF risk. Yet, the mechanisms underlying JNK2 activation in the aged heart remain unclear. Emerging evidence suggests that organ crosstalk critically contributes to the development of heart diseases. Interestingly, increased AF episodes were clinically observed in patients with active gastrointestinal (GI) diseases (with a hallmark of enhanced intestinal epithelial barrier permeability (‘leaky gut’), but reduced AF during remission. While both GI dysfunction and enhanced AF risk are seen in aged humans and animal models, whether aging-associated leaky gut leads to AF pathogenesis through activated JNK2 remains unknown. Methods: To assess the leaky gut and AF link, young (Yg, 2 mo) wildtype (WT) and JNK2dn mice (cardiac-specific overexpression of inactive dominant negative (dn) JNK2) were used for aged fecal matter transplant (FMT), while aged (Ag, 24 mo) mice were transplanted with Yg fecal matter to rescue aging-associated AF. Atrial tachycardia/fibrillation (AT/AF) incidence was measured using our well-established protocol, and GI permeability was measured using a serum dextran (4-kDa) FITC fluorescence assay 7 days post-FMT. Results: Aged WT mice had an elevated FITC level (4.9±1.5 µg/ml vs 0.98±0.04 µg/ml; n=11,8; p<0.01) with increased AT/AF inducibility compared to Yg mice (n=7,10; p<0.05). Interestingly, Yg WT recipients subjected to aged FMT (Ag-to-Yg) exhibited an ~3-fold increase in GI permeability (n=14; p<0.01) and significantly enhanced AT/AF inducibility relative to Yg sham controls (8 of 13 vs 0 of 10; p<0.05), while Yg-to-Yg FMT did not alter GI permeability and AT/AF inducibility in Yg recipients (0 of 5, p=NS). Strikingly, cardiac-specific JNK2 inhibition prevented aged-FMT-caused AT/AF in Yg JNK2dn recipient mice (0 of 10; p<0.01), suggesting that activated cardiac JNK2 underlies leaky gut-evoked AF in aging. Further, Yg-to-Ag FMT eliminated aged-associated AT/AF inducibility in aged recipients (0 of 6). Conclusion: Aging-associated GI dysfunction enhances cardiac JNK2 activation, which in turn drives AF risk. Targeting cardiac JNK2 could be a novel anti-AF therapeutic strategy.

Abstract Mo065: An Anti-arrhythmic Action and Novel Molecular Mechanisms of Alda-1 in Holiday Heart Syndrome

Introduction: Holiday Heart Syndrome (HHS) is caused by excessive binge alcohol intake. Atrial fibrillation (AF) is the most common arrhythmia in HHS patients. With a worldwide rising trend in heavy alcohol consumption despite significant prevention efforts, effective drugs against alcohol-evoked AF are in urgent need. Methods: We assessed the effect of Alda-1, a cardiac protective agent, on mitigating binge alcohol-evoked AF and alcohol-activated stress kinase JNK2 in 50mM alcohol-exposed (24hr) H9c2 differentiated myocytes and in a well-characterized HHS mouse model (2g/kg ethanol i.p., 4 injections, every other day). Alda-1’s effect on alcohol-evoked RyR2 channel-mediated Ca 2+ waves/sparks & tachycardia/fibrillation (AT/AF) incidence were measured in intact mouse atria. RyR2 channel open probability was assessed in human RyR2 single-channel recordings. Results: We found that Alda-1 significantly reduced atrial arrhythmia inducibility in HHS mouse atria, as evidenced by a decreased incidence of alcohol-evoked AT/AF (0 vs. 0.21 incidences/pacing attempts/animal; n=6, 8). Alda-1 is an agonist of aldehyde dehydrogenase 2 (ALDH2; a key enzyme in alcohol detoxification), which inhibits cellular apoptosis. We found that ALDH2 was increased by 42%±6 in HHS mice compared to controls, and which remained elevated upon Alda-1 treatment (n=6,7,7; p<0.05). HHS hearts showed unchanged apoptotic signaling pathways, suggesting alternative mechanisms in AF genesis. Our lab recently revealed a critical role of activated cardiac stress kinase JNK2 in AF risk. Intriguingly, Alda-1 suppressed alcohol-activated JNK2 by 70%±13 (immunoprecipitated JNK2-specific activity; n=9,9, p<0.001) (but not JNK1, the other cardiac JNK isoform) in cells, while JNK2 inhibition alleviated alcohol-evoked RyR2 channel dysfunction in human RyR2 channels as well as Ca 2+ -triggered atrial arrhythmic activities and AT/AF (0 out of 8; p<0.05) in intact mouse hearts. Conclusion: Alda-1 effectively mitigates binge alcohol-evoked atrial arrhythmogenesis by suppressing JNK2 activity independently of an ALDH2-mediated anti-apoptosis effect. Our findings highlight the potential of Alda-1 as a therapeutic agent for the increasing incidence of alcohol-evoked AF.

Abstract Mo060: SPEG mediates increased atrial fibrillation incidence in chronic kidney disease

Introduction: Chronic kidney disease (CKD) is a major public health problem. CKD is a risk factor of cardiovascular morbidity and mortality due to the increased incidence of atrial fibrillation (AF). AF onset is known to be the consequence of cardiomyocyte intracellular calcium (Ca 2+ ) mishandling where increased ryanodine receptor type 2 (RyR2) activity causes triggered activity. RyR2 activity is regulated by phosphorylation of serine 2367 (S2367) by the ‘striated muscle preferentially expressed protein’ (SPEG). Reduced RyR2 phosphorylation at S2367 increases the risk of AF. We hypothesized that changes in atrial SPEG underly the increased risk of AF in CKD patients. Methods: The experimental 5/6 nephrectomy model was used to mimic CKD disease in mice. AF inducibility was determined using intracardiac programmed electric stimulation. Echocardiography was used to analyze cardiac structure. RYR2 phosphorylation and SPEG levels were measured by western blotting. Intracellular Ca2+ dynamics were assessed by confocal microscopy. Results: CKD mice showed increased serum phosphate (14.1±1.4 vs 9.3±0.4mg/dL; p<0.01), creatinine (0.4±0.1 vs 0.8±0.3 mg/dL; p<0.001) and urea (30.5±1.1 vs 20.9±0.4 mg/dL; p<0.001). AF incidence was 4-fold higher in CKD respect sham mice (60 vs 14.2%; p<0.05). CKD mice showed longer P waves (14.3±0.4 vs 12.5±0.3; p<0.01) and greater increase of left atrial size than Sham mice (35.0±7.5 vs 13.9±4.6; p<0.05). Ejection fraction was reduced in CKD mice after 6 weeks of CKD progression (57.9±0.6 vs 61.7±0.8%; p<0.001) while no changes were observed in Sham mice. SPEG levels were decreased in atria from CKD mice compared to sham (0.64±0.11 vs 1.19±0.13; p<0.05). RyR2 phosphorylation at S2367 was reduced in CKD mice atria (0.66±0.16 vs 1.25±0.26 in sham; p=0.098). Atrial cardiomyocytes from CKD mice exhibited altered Ca 2+ handling, with decreased SERCA activity (p<0.05), increased spark-mediated diastolic Ca 2+ leak (p<0.01) and increased NCX activity (p<0.05). Finally, CKD-induced AF onset was prevented in a mice with a mutation that mimics RYR2 phosphorylation at SPEG site (S2367D mice) Conclusion: This study shows for the first time that SPEG levels are decreased in atria from CKD mice what induces increased RyR2 activity leading to increased AF incidence. By conserving RYR2 phosphorylation at Ser2367, CKD-induced AF was prevented. Thus, we propose SPEG as a possible therapeutic target to reduce the increased incidence of AF in CKD patients.

Abstract Tu040: A Novel Anti-Thrombotic and Anti-AF Drug without an Adverse Bleeding Problem

Introduction: Aging is an independent risk factor of atrial fibrillation (AF), which leads to a high mortality due to thromboembolic stroke. But available antithrombotic therapies are limited for the aged AF patients due to aging-associated bleeding risk. We recently revealed critical roles of activated cardiac stress kinase JNK2 in both enhanced AF risk and thrombogenesis in aging through a mechanism of heart-platelet crosstalk. Here, we assessed anti-thrombotic potentials of JNK2 inhibition. Methods: Young (Yg) and aged (2 vs 24 mo) wildtype (WT) mice with and without a JNK2-specific inhibitor (JNK2I, 5 mg/kg i.p.; every other day/4 doses) or meloxicam (0.5 mg/kg/day, i.p.; five days) treatment were used for in vivo FeCl 3 -induced carotid artery occlusion (thrombus formation) and tail bleeding assays. The effects of cardiac JNK2-specific inhibition in thrombogenesis and bleeding were assessed in our unique cardiac-specific mice of MKK7D (inducible overexpression of active MKK7D, a JNK upstream activator) and MKK7D-JNK2dn (overexpressed inactive dominant negative (dn) JNK2 to competitively inhibit endogenous JNK2 in MKK7D mice). Results: Aged mice had a shortened artery occlusion time compared to Yg (5.8±0.2 min vs. 7.1±0.2 min, p<0.001, n=12,7). JNK2I reversed the occlusion time in aged mice to that seen in Yg (p=NS, n=8,7). Yg MKK7D mice also showed a shortened occlusion time compared to WT-controls (p<0.001, n=9,8) that was rescued by cardiac-specific JNK2 inhibition in MKK-JNK2dn mice (p=NS, n=5,8), suggesting a key role of cardiac JNK2 in thrombus formation. Next, we found that 40% of aged WT mice had continuous bleeding compared to its absence in Yg WT. However, meloxicam (an anti-platelet NSAID drug) increased continuous bleeding risk in both aged (83% had it) and Yg (20%) and prolonged the initial clotting time in aged mice (385±56s vs 84±18s in aged controls; p<0.001, n=8,6). In contrast, JNK2I eliminated this bleeding issue, evidenced from the absence of continuous bleeding and shortened initial clotting time compared to aged controls (p=NS, n=8,8). Conclusion: Heart JNK2 enhances thrombotic risk in the blood. JNK2 inhibition could be a promising anti-thrombotic and anti-AF therapeutic approach without adverse bleeding for aged AF patients.

Treatment of subclinical hyperthyroidism in patients older than 50 years: A randomized controlled study.

Subclinical hyperthyroidism (SCH) is common and associated with atrial fibrillation (AF) risk in the elderly. Current guidelines rely on a low level of evidence. Randomized clinical trial including patients 50 years and older, with TSH <0.4 mU/L and normal thyroid hormone concentrations. All patients showed autonomy on thyroid scan. They were randomized either to receive radioiodine (I131) or to be monitored and treated only if they underwent AF or evolved towards overt hyperthyroidism. Primary outcome was the onset of new AF. Secondary outcomes were treatment-induced hypothyroidism rate and health-related quality of life. 144 patients (mean age 65.3±8.9y, 76% female) were randomized, 74 to surveillance and 70 to treatment. Four patients in the surveillance group and one in the treatment group developed AF (p=0.238). However, the patient who developed AF in the treatment group maintained TSH <0.4 mU/L at AF onset. A post-hoc analysis was carried out and showed that when normalization of TSH was considered, the risk of AF was significantly reduced (p=0.0003). In the surveillance group, several patients showed no classical characteristics associated with AF risk, including age>65y or TSH<0.1mU/L. Of 94 patients treated using radioiodine, 25% developed hypothyroidism during follow-up. Due to recruitment difficulties this study failed to demonstrate that SCH treatment can reduce significantly the incidence of AF in patients older than 50 years with thyroid autonomy even if all the patients who developed AF maintained TSH <0.4 mU/L. This result must be balanced with the increased risk of radioiodine-induced hypothyroidism.

Calcium-mediated DAD in membrane potentials and triggered activity in atrial myocytes of ETV1f / fMyHCCre /+ mice.

The E-twenty-six variant 1 (ETV1)-dependent transcriptome plays an important role in atrial electrical and structural remodelling and the occurrence of atrial fibrillation (AF), but the underlying mechanism of ETV1 in AF is unclear. In this study, cardiomyocyte-specific ETV1 knockout (ETV1f/fMyHCCre/+, ETV1-CKO) mice were constructed to observe the susceptibility to AF and the underlying mechanism in AF associated with ETV1-CKO mice. AF susceptibility was examined by intraesophageal burst pacing, induction of AF was increased obviously in ETV1-CKO mice than WT mice. Electrophysiology experiments indicated shortened APD50 and APD90, increased incidence of DADs, decreased density of ICa,L in ETV1-CKO mice. There was no difference in VINACT,1/2 and VACT,1/2, but a significantly longer duration of the recovery time after inactivation in the ETV1-CKO mice. The recording of intracellular Ca2+ showed that there was significantly increased in the frequency of calcium spark, Ca2+ transient amplitude, and proportion of SCaEs in ETV1-CKO mice. Reduction of Cav1.2 rather than NCX1 and SERCA2a, increase RyR2, p-RyR2 and CaMKII was reflected in ETV1-CKO group. This study demonstrates that the increase in calcium spark and SCaEs corresponding to Ca2+ transient amplitude may trigger DAD in membrane potential in ETV1-CKO mice, thereby increasing the risk of AF.

Prognostic importance of ischemic heart disease for patients with atrial fibrillation undergoing catheter ablation

BackgroundIschemic heart disease (IHD) has been linked to an increased risk of atrial fibrillation (AF). However, data are sparse regarding the role of IHD in AF recurrence after catheter ablation. ObjectiveWe sought to investigate whether preexisting or new-onset IHD is associated with a greater risk of AF recurrence after ablation. MethodsWith use of Danish nationwide registries, all patients undergoing first-time AF ablation in Denmark from 2010 to 2020 were identified. The primary outcome was AF recurrence defined by AF-related hospital admission or antiarrhythmic drug use within 1 year after ablation excluding a 3-month blanking period. IHD was defined as an International Classification of Diseases, Tenth Revision diagnosis of IHD or prior coronary revascularization. ResultsOf 12,162 patients undergoing first-time ablation for AF (mean age, 62 years; 30% female), 20% had preexisting IHD. Preexisting IHD was associated with an increased risk of AF recurrence in univariable log-binomial logistic regression (relative risk, 1.09; 95% CI, 1.04–1.14; P < .001). However, after multivariable adjustment including procedural year, preexisting IHD was no longer associated with an increased risk of AF recurrence (relative risk, 1.02; 95% CI, 0.97–1.06; P = .42). In a nested case-control study of those without preexisting IHD before ablation (n = 9778), newly diagnosed IHD after ablation was associated with an increased risk of AF recurrence in multivariable analysis (hazard ratio, 3.03; 95% CI, 1.84–4.99; P < .001). ConclusionThe presence of IHD does not appear to reduce the effectiveness of AF ablation procedures. However, the emergence of IHD after AF ablation may serve as a trigger for AF that is insufficiently suppressed by prior ablation.

Novel Genes Associated With Atrial Fibrillation and the Predictive Models for AF Incorporating Polygenic Risk Score and PheWAS-Derived Risk Factors

BackgroundAtrial fibrillation (AF), the most common atrial arrhythmia, presents with varied clinical manifestations. Despite the identification of genetic loci associated with AF, particularly in specific populations, research within Asian ethnicities remains limited. In this study we aimed to develop predictive models for AF using AF-associated single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) on a substantial cohort of Taiwanese individuals, to evaluate the predictive efficacy of the model. MethodsThere were 75,121 subjects, that included 5694 AF patients and 69,427 normal control subjects with GWAS data, and we merged polygenic risk scores from AF-associated SNPs with phenome-wide association study-derived risk factors. Advanced statistical and machine learning techniques were used to develop and evaluate AF predictive models for discrimination and calibration. ResultsThe study identified the top 30 significant SNPs associated with AF, predominantly on chromosomes 10 and 16, implicating genes like NEURL1, SH3PXD2A, INA, NT5C2, STN1, and ZFHX3. Notably, INA, NT5C2, and STN1 were newly linked to AF. The GWAS predictive power using polygenic risk score-continuous shrinkage analysis for AF exhibited an area under the curve of 0.600 (P < 0.001), which improved to 0.855 (P < 0.001) after adjusting for age and sex. Phenome-wide association study analysis showed the top 10 diseases associated with these genes were circulatory system diseases. ConclusionsIntegrating genetic and phenotypic data enhanced the accuracy and clinical relevance of AF predictive models. The findings suggest promise for refining AF risk assessment, enabling personalized interventions, and reducing AF-related morbidity and mortality burdens.

Characterizing atrial fibrillation in patients with and without heart failure across the ejection fraction spectrum: Incidence, prevalence, and treatment strategies.

Heart failure (HF) and atrial fibrillation (AF) often coexist. We explored AF incidence, prevalence, and treatment strategies in patients with versus without HF across the ejection fraction (EF) spectrum. We analysed patients with HF from the Swedish HF Registry (1 December 2005-31 December 2021), matched 1:1 by sex, age, and county of residence to patients without HF from Statistics Sweden. Two study cohorts were derived (i) to assess AF prevalence and treatments, and (ii) to evaluate AF incidence and related predictors. Overall, 195 106 patients were considered, 50% of them with HF (of whom 54% with HF with reduced [HFrEF], 23% mildly reduced [HFmrEF], and 23% with preserved EF [HFpEF]). From 2006 to 2021, AF prevalence increased in both patients with (57% to 58%) and without HF (8% to 11%). HF patients, particularly if with HFrEF, were more likely receiving AF treatments than those without HF. Over time, antiarrhythmic use decreased, while rate control drugs and oral anticoagulant use, and AF-related procedures increased, regardless of HF and EF. During a median follow-up of 3.7 years, in 86 210 patients without AF, incident AF risk was two-fold higher in HF versus non-HF (hazard ratio [HR] 2.76, 95% confidence interval [CI] 2.45-3.12), highest in HFpEF (HR 3.12, 95% CI 2.65-3.67) versus HFrEF (HR 2.68, 95% CI 2.34-3.06) and HFmrEF (HR 2.53, 95% CI 2.17-2.94). Atrial fibrillation prevalence, anticoagulant use, and AF-related procedures increased over time regardless of HF, with HF patients more likely receiving AF treatments. In HF, despite higher AF prevalence and incidence in HFpEF, AF treatment use remained modest, calling for further implementation.

Titin truncating variants, cardiovascular risk factors and the risk of atrial fibrillation and heart failure.

High-proportion spliced-in (hiPSI) titin truncating variant (TTNtv) carriers have a higher risk of atrial fibrillation and heart failure1. However, the role of cardiovascular risk factors in modifying the risk of atrial fibrillation and heart failure attributed to hiPSI TTNtv carriers is unknown. Here, we investigate the role of cardiovascular risk, quantified using the pooled cohort equations (PCEs), in influencing the hazard of outcomes attributed to hiPSI TTNtvs among UK Biobank participants without baseline cardiovascular disease. The cohort was stratified based on hiPSI TTNtv carrier status and cardiovascular risk (low: <5%, intermediate: 5.0-7.5% and high: >7.5%). The primary outcome was a composite of atrial fibrillation, heart failure or death. TTNtv noncarriers with low cardiovascular risk were used as the reference group for all analyses. Among 179,752 participants (median age: 56 (49, 62) years; 57.5% female), the risk of the primary outcome was lower in hiPSI TTNtv carriers with low cardiovascular risk (adjusted hazard ratio: 2.23 (95% confidence interval: 1.62-3.07)) than those with high cardiovascular risk (adjusted hazard ratio: 8.21 (95% confidence interval: 6.63-10.18)). A favorable cardiovascular risk factor profile may partially offset the risk of clinical outcomes among hiPSI TTNtv carriers.

Inverse relationship between LDL-C/HDL-C ratio and atrial fibrillation in chronic kidney disease patients

Atrial fibrillation (AF) is more prevalent in individuals with chronic kidney disease (CKD) compared to the general population. While a potential inverse correlation between lipid levels and AF has been proposed, it remains unclear if this relationship applies to CKD patients. This study examined the connection between the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-C/HDL-C) and the likelihood of AF in CKD patients. Data was gathered from 21,091 consecutive CKD patients between 2006 and December 31, 2015. We examined the link between the LDL-C/HDL-C ratio and AF in CKD patients through binary logistic regression, as well as various sensitivity and subgroup analyses. The dataset that backs up these analyses is available at: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230189. Of the 21,091 CKD patients, 211 (1.00%) were diagnosed with AF. The cohort, predominantly male (79.93%), had a mean age of 60.89 ± 10.05 years. The mean LDL-C/HDL-C ratio was 1.39 ± 0.35. After adjusting for covariates, a significant inverse association was observed between the LDL-C/HDL-C ratio and the incidence of AF in CKD patients (OR = 0.422, 95% CI 0.273–0.652, P = 0.00010). The robustness of these findings was confirmed through sensitivity analysis. Subgroup analysis revealed a strong correlation between the LDL-C/HDL-C ratio and incident AF in patients without hypertension (HR = 0.26, 95% CI 0.15–0.45). Conversely, this association was absent in hypertensive patients (HR = 1.09, 95% CI 0.54–2.17). Our research shows an independent inverse correlation between the LDL-C/HDL-C ratio and the risk of AF in CKD patients. It is advised to refrain from excessively aggressive reduction of LDL levels in CKD patients, as this could elevate the risk of developing AF.

Effect of different hypoglycemic drugs and insulin on the risk of new-onset atrial fibrillation in people with diabetes: a network meta-analysis

ObjectiveDiabetes is considered a significant risk factor for the development of atrial fibrillation/flutter (AF/AFL). However, there is still insufficient evidence to determine the varying effects of different hypoglycemic drugs (HDs) on the incidence of new-onset AF/AFL in diabetic patients. To address this gap, we conducted a network meta-analysis to investigate whether various HDs have different effects on the risk of new-onset AF/AFL compared with insulin.MethodWe conducted a comprehensive search in PubMed, EMBASE, Cochrane Library, and Web of Science to identify all clinical trials investigating the association between various HDs or insulin and incident AF/AFL up until April 1, 2024. Bayesian random-effects model was used for network meta-analysis, and the results were expressed as relative risk (RR) and 95% confidence interval (CI).ResultAfter searching 2070 articles, a total of 12 studies (2,349,683 patients) were included in the network meta-analysis. The treatment regimen comprised insulin and 8 HDs hypoglycemic drugs, which are sodium-dependent glucose transporters 2 inhibitor (SGLT2i), glucagon-like peptide 1 receptor agonist (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), metformin (Met), sulfonylureas (SU), non-sulfonylureas (nSU), thiazolidinedione (TZD) and α-glycosidase inhibitors (AGI). The use of SGLT2i [RR 0.23, 95%CI (0.11, 0.49)], GLP-1RA [RR 0.28, 95%CI (0.13, 0.57)], and DPP4i [RR 0.34, 95%CI (0.17, 0.67)] demonstrated significant efficacy in reducing the incidence of new-onset AF/AFL when compared to insulin. When HDs were compared in pairs, SGLT2i is more effective than Met [RR 0.35, 95% CI (0.19, 0.62)], SU (RR 0.27, 95% CI (0.14, 0.51)], nSU [RR 0.28, 95% CI (0.08, 0.95)], TZD [RR 0.34, 95% CI (0.17, 0.7)], GLP-1RA is more effective Met [RR 0.42, 95% CI (0.25, 0.71)], SU (RR 0.33, 95% CI (0.18, 0.6)], TZD [RR 0.41, 95% CI (0.21, 0.82)], while Met[RR 1.98, 95% CI (1.23, 3.23)], SU [RR 2.54, 95% CI (1.46, 4.43)], TZD [RR 2.01, 95% CI (1.05, 3.79)] was not as effective as DPP4i.ConclusionSGLT-2i, GLP-1RA, and DPP4i showed a superior efficacy in reducing the risk of new-onset AF/AFL compared to insulin therapy.

Apixaban plasma concentrations before and after catheter ablation for atrial fibrillation.

Catheter ablation in patients with atrial fibrillation is associated with a transient increase in thromboembolic risk and adequate anticoagulation is highly important. When patients are anticoagulated with apixaban, monitoring of plasma concentrations of the drug is not routinely performed. This study aimed to assess the influence of clinical patient characteristics, concomitant drug treatment and self-reported adherence on apixaban concentrations, and to describe the intra- and inter-individual variability in apixaban concentrations in this group of patients. Method Apixaban concentrations from 141 patients were measured in plasma one week before ablation and two, six and ten weeks after ablation, employing ultra-high performance liquid chromatography coupled with tandem mass spectrometry. In samples not obtained at trough, apixaban concentrations were adjusted to trough levels. Self-reported adherence was registered by means of the 8-item Morisky Medication Adherence Scale before and after ablation. There were statistically significant, positive correlations between apixaban concentrations and increased age, female sex, lower glomerular filtration rate, higher CHA2DS2-VASc score, use of cytochrome P450 3A4 and/or p-glycoprotein inhibitors, and use of amiodarone. Self-reported adherence was generally high. The mean intra-individual and inter-individual coefficients of variation were 29% and 49%, respectively. In patients undergoing catheter ablation for atrial fibrillation, age, sex, renal function, interacting drugs and cerebrovascular risk profile were all associated with altered plasma apixaban concentration. In this group of patients with a generally high self-reported adherence, intra-individual variability was modest, but the inter-individual variability was substantial, and similar to those previously reported in other patient apixaban-treated populations. If a therapeutic concentration range is established, there might be a need for a more flexible approach to apixaban dosing, guided by therapeutic drug monitoring.

Exploring the impact of electrocardiographic parameters on the risk of common arrhythmias: a two-sample Mendelian randomization study.

Observational studies have shown that heart rate (HR), heart rate variability (HRV), P-wave terminal force, P-wave duration, T-wave amplitude and PR interval are associated with risk factors for atrial fibrillation (AF) or bradycardia. Arrhythmias are associated with many causes of hospitalization. However, observational studies are susceptible to confounding factors that have not yet been identified. The objective of this study was to clarify the causal relationships by Mendelian randomization analysis. We conducted a two-sample and multivariate Mendelian randomization (MVMR) analysis using genome-wide association study (GWAS) data from a European population to assess the total and direct causal effects of HR, three HRV traits, P-wave terminal force, P-wave duration, T-wave top amplitude in five-lead modes, and the PR interval on the risk of AF (N=191,205), bradycardia (N=463,010), and supraventricular tachycardia (SVT) (N=463,010). The results of the univariate MR analysis revealed the following significant causal effects: the higher the genetically predicted PR interval, the lower the risk of AF; the higher the HR and T-wave top amplitude (aVR leads and V3 + V4 + aVL leads), the lower the risk of bradycardia; and the higher HR and the lower PR interval, the higher the risk of SVT. The multivariate MR results indicated that the HRV_standard deviation of the normal-to-normal (SDNN) interval had an independent causal effect on the risk of AF [odds ratio (OR): 0.515; 95% confidence interval (CI): 0.278-0.954; P=0.03], and the T-wave top amplitude in the aVR leads (OR: 0.998; 95% CI: 0.996-0.999; P<0.001) and the HRV_SDNN (OR: 0.988; 95% CI: 0.976-1.000; P=0.045) had independent causal effects on the risk of bradycardia. The HRV_SDNN had an independent causal effect on AF, while the HRV_SDNN and T-wave top amplitude in the aVR leads had independent causal effects on bradycardia, which suggests that some of the electrocardiographic parameters have preventive effects on the incidence of AF and bradycardia.

Left Atrial Appendage Occlusion as a Strategy for Reducing Stroke Risk in Nonvalvular Atrial Fibrillation.

Nonvalvular atrial fibrillation (AF) is a common rhythm disorder of middle-aged to older adults that can cause ischemic strokes and systemic embolism. Stroke prevention is a crucial aspect of management, considering the increasing AF population and the associated morbidity and mortality. The left atrial appendage (LAA) has been identified as a predominant source of AF-associated thrombus and stroke, with at least 90% of the thrombi originating from this anatomical structure. Lifelong use of oral anticoagulants reduces the risk of these ischemic events but increases the risk of major and clinically relevant hemorrhages. In addition, these medications also require strict compliance for efficacy and have high failure rates in higher-risk patients. LAA occlusion (LAAO) has emerged as an alternative strategy for stroke prevention with encompassing various percutaneous and surgical techniques. Randomized controlled trials evaluating this intervention have shown promising results in stroke reduction replacing anticoagulation therapy. In this review, we aim to provide a comprehensive overview on the anatomy of the LAA and its role in thrombus formation, the emergence of various LAAO techniques and devices, and provide evidence on the role of LAAO in the reduction of stroke risk among patients with nonvalvular AF.