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Background: Left atrial (LA) low-voltage areas (LVAs) are frequently observed in patients with atrial fibrillation (AF) and may predict AF recurrence after catheter ablation.Objective: The aim of this study was to develop and validate a clinical tool to identify LVAs that are associated with AF recurrence after pulmonary vein isolation (PVI).Methods: In a cohort of 238 patients, voltage maps were created during LA procedures. LVAs were defined as areas with electrogram amplitudes <0.5 mV. On the basis of regression analysis, predictors of LA substrate were identified. These parameters were used to establish a dedicated risk score (DR-FLASH score, based on diabetes mellitus, renal dysfunction, persistent form of AF, LA diameter >45 mm, age >65 years, female sex, and hypertension). This risk score was then prospectively validated in a multicenter cohort of 180 patients. The association of the score with long-term recurrence of atrial arrhythmias after circumferential PVI was tested in a retrospective cohort of 484 patients.Results: The DR-FLASH score effectively identified LVA substrate (C statistic = 0.801, P < .001). In the prospective multicenter validation cohort, the predictive value of the DR-FLASH score was confirmed (C statistic = 0.767, P < .001). The probability for the presence of LA substrate increased by a factor of 2.2 (95% confidence interval [CI] 1.6-2.9, P < .001) with each point scored. Furthermore, the risk of AF recurrence after PVI increased by a factor of 1.3 (95% CI 1.1-1.5, P < .001) with every additional point and was almost 2 times higher in patients with a DR-FLASH score >3 (odds ratio 1.7, 95% CI 1.1-2.8, P = .026).Conclusion: The DR-FLASH score may be useful to identify patients who may require extensive substrate modification instead of PVI alone. [ABSTRACT FROM AUTHOR]

Assessing Stroke risK by LAA Anatomy (ASK LAA) Introduction In patients with atrial fibrillation (AF), LAA morphology has been suggested to modify thromboembolic event (TE) risk. We tested the hypothesis that TE in low-risk patients is associated with LAA characteristics. Methods Of 2,069 patients who underwent AF ablation, 25 (1.2%) had a prior TE and a low CHA2DS2-VASc score (≤1). Those patients were matched for the CHA2DS2-VASc criteria with 75 event­free patients and CT data were compared. LAA measurements, morphology (Cactus, Chicken-Wing, Windsock, Cauliflower), and takeoff of the superior and inferior edge in relation (higher or lower) to the respective takeoff of the adjacent pulmonary vein (PV) were determined. LAA flow in relation to heart rate was also compared. Results Univariate analysis showed that TE patients had a higher incidence of superior LAA takeoff (i.e., higher than the left superior PV; 28% vs. 4%, P = 0.002) and a higher incidence of hyperlipidemia (40% vs. 17%, P = 0.028), while LAA morphologies, inferior takeoff, and other LAA characteristics were similar between groups. Logistic regression revealed that a superior LAA takeoff (OR: 9.1, 95% CI: 2.1-38.6, P = 0.003) was the only independent predictor of TE. There was a negative correlation between heart rate and LAA flow (r = -0.2 cm/s pro bpm, P = 0.048), that was even more pronounced for the superior LAA takeoff (r = -0.67 cm/s pro bpm, P = 0.035). Conclusion A higher LAA takeoff is associated with a tachycardia-mediated thrombogenic flow and an increased thromboembolic risk. These findings may have implications for anticoagulation management of AF patients with low CHA2DS2-VASc scores and higher LAA takeoff. [ABSTRACT FROM AUTHOR]

Background Numerous electrocardiographic (ECG) criteria have been proposed to identify localization of outflow tract ventricular arrhythmias (OT-VAs); however, in some cases, it is difficult to accurately localize the origin of OT-VA using the surface ECG. Objective The purpose of this study was to assess a simple criterion for localization of OT-VAs during electrophysiology study. Methods We measured the interval from the onset of the earliest QRS complex of premature ventricular contractions (PVCs) to the distal right ventricular apical signal (the QRS-RVA interval) in 66 patients (31 men aged 53.3 ± 14.0 years; right ventricular outflow tract [RVOT] origin in 37) referred for ablation of symptomatic outflow tract PVCs. We prospectively validated this criterion in 39 patients (22 men aged 52 ± 15 years; RVOT origin in 19). Results Compared with patients with RVOT PVCs, the QRS-RVA interval was significantly longer in patients with left ventricular outflow tract (LVOT) PVCs (70 ± 14 vs 33.4±10 ms, P < .001). Receiver operating characteristic analysis showed that a QRS-RVA interval ≥49 ms had sensitivity, specificity, and positive and negative predictive values of 100%, 94.6%, 93.5%, and 100%, respectively, for prediction of an LVOT origin. The same analysis in the validation cohort showed sensitivity, specificity, and positive and negative predictive values of 94.7%, 95%, 95%, and 94.7%, respectively. When these data were combined, a QRS-RVA interval ≥49 ms had sensitivity, specificity, and positive and negative predictive values of 98%, 94.6%, 94.1%, and 98.1%, respectively, for prediction of an LVOT origin. Conclusion A QRS-RVA interval ≥49 ms suggests an LVOT origin. The QRS-RVA interval is a simple and accurate criterion for differentiating the origin of outflow tract arrhythmia during electrophysiology study; however, the accuracy of this criterion in identifying OT-VA from the right coronary cusp is limited. [ABSTRACT FROM AUTHOR]

Background Occlusion of the right coronary artery (RCA) may promote atrial fibrillation (AF) by creating a right atrial substrate. However, the presence and extent of coronary artery disease (CAD) is usually not considered to tailor AF ablation strategies. This study was aimed to analyze the possible association between the presence and extent of CAD and rhythm outcomes of left-atrial AF catheter ablation. Methods 1310 patients (60 ± 10 years, 67% males, 63% paroxysmal AF) from The Leipzig Heart Center AF Ablation Registry undergoing de novo AF catheter ablation were included. CAD was defined as stenosis ≥ 50% in the left main coronary artery and ≥ 70% in one or several of the major coronary arteries. AF recurrences were defined as any atrial arrhythmia lasting > 30 s and occurring within the first week (early recurrences, ERAF) or between 3 and 12 months (late recurrences, LRAF) after ablation and were assessed with serial 7-day Holter ECG. Results 152 patients (11.6%) had significant CAD; 89 (59%) had one, 35 (23%) two and 28 (18%) three vessel disease; 72 (47%) patients had RCA involvement. Occurrence of AF recurrences was comparable in CAD (p = 0.625 and 0.568 for ERAF and LRAF, respectively). Among patients with CAD, neither the location (RCA versus non-RCA) nor the extent of CAD (single versus multiple vessel disease) was associated with rhythm outcomes after AF catheter ablation (all p > 0.05). Conclusion The presence and extent of CAD seem not to impact on rhythm outcome of AF catheter ablation in the entire cohort. [ABSTRACT FROM AUTHOR]

Background Renal impairment is associated with poor prognosis in the setting of atrial fibrillation (AF). While AF catheter ablation is an effective treatment modality for AF burden reduction and improvement of symptoms, changes in renal function after catheter ablation and their association with rhythm outcome have not been studied in a large contemporary AF ablation cohort. Objective To determine the association between CHADS2 and CHA2DS2-VASc scores and arrhythmia recurrences with changes in renal function following AF catheter ablation. Methods Estimated glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation at baseline and during follow-up in 783 patients undergoing de novo AF catheter ablation. Complete rhythm follow-up was achieved in 626 patients (80%) using serial 7-day Holter ECG. Results The study population (n=783, 61±10 years, 64% men, 57% paroxysmal AF) was followed up at median 20 (IQR 12-27) months. Baseline eGFR correlated with CHADS2 (ß=--0.258, p<0.001) and CHA2DS2-VASc scores (ß=-0.434, p<0.001). On multivariable analyses, eGFR changes were associated with AF recurrences (B= -0.136, p=0.014), CHADS2 (B=-0.062, p=0.035) and CHA2DS2-VASc scores (B=-0.057, p=0.003). Conclusions In patients after AF catheter ablation, eGFR changes during mid-term follow-up are associated with AF recurrences, CHADS2 and CHA2DS2-VASc scores. [ABSTRACT FROM AUTHOR]

Background: This pilot study investigated the association between heat shock protein 70 (HSP70) and anti-HSP70 antibodies as well as their changes and rhythm outcome after atrial fibrillation (AF) catheter ablation. Methods: We studied 67 patients with AF (59±11 years, 66% male, 66% lone AF) undergoing catheter ablation. Circulating HSP70 and anti-HSP70 antibody levels were quantified using commercially available assays before and 6 months after catheter ablation. Serial 7-day Holter ECGs were used to detect AF recurrences. Results: At baseline, HSP70 was detectable in 14 patients (21%), but there was no correlation between clinical or echocardiographic variables and the presence or the level of HSP70. In contrast, patients with paroxysmal AF (n=39) showed lower anti-HSP70 antibodies (median [IQR] of 43 [28 - 62] µg/ml) than patients with persistent AF (n=28; 53 [41 - 85] µg/ml, p=0.035). Using multivariable regression analysis, AF type was the only variable associated with anti-HSP70 antibodies (Beta=0.342, p=0.008). At 6 months, HSP70 was present in 27 patients (41%, p<0.001 vs. baseline). Similarly, there was an increase of anti-HSP70 antibodies (48 [36 - 72] vs. 57 [43 - 87] µg/ml, p<0.001). AF recurrence rates were higher in patients with HSP70 increase =0.025 ng/ml (32 vs. 11%, p=0.038) or anti-HSP70 increase =2.5 µg/ml (26 vs. 4%, p=0.033). Conclusions: HSP70 and anti-HSP70 antibodies may - at least in part - be associated in the progression of AF and AF recurrence after catheter ablation [ABSTRACT FROM AUTHOR]

Although the main focus in this study was the role of LA-EF in HFpEF patients, we would like to highlight the LA-EF importance in patients with AF, as both conditions - HFpEF and AF - frequently coexist. Summarizing, LA function and NT-proANP might be considered as biomarkers linking AF progression and HFpEF patients, indicating a poorer outcome and advanced disease stages. [Extracted from the article]

Background: eCohort studies offer an efficient approach for data collection. However, eCohort studies are challenged by volunteer bias and low adherence. We designed an eCohort embedded in the Framingham Heart Study (eFHS) to address these challenges and to compare the digital data to traditional data collection.Objective: The aim of this study was to evaluate adherence of the eFHS app-based surveys deployed at baseline (time of enrollment in the eCohort) and every 3 months up to 1 year, and to compare baseline digital surveys with surveys collected at the research center.Methods: We defined adherence rates as the proportion of participants who completed at least one survey at a given 3-month period and computed adherence rates for each 3-month period. To evaluate agreement, we compared several baseline measures obtained in the eFHS app survey to those obtained at the in-person research center exam using the concordance correlation coefficient (CCC).Results: Among the 1948 eFHS participants (mean age 53, SD 9 years; 57% women), we found high adherence to baseline surveys (89%) and a decrease in adherence over time (58% at 3 months, 52% at 6 months, 41% at 9 months, and 40% at 12 months). eFHS participants who returned surveys were more likely to be women (adjusted odds ratio [aOR] 1.58, 95% CI 1.18-2.11) and less likely to be smokers (aOR 0.53, 95% CI 0.32-0.90). Compared to in-person exam data, we observed moderate agreement for baseline app-based surveys of the Physical Activity Index (mean difference 2.27, CCC=0.56), and high agreement for average drinks per week (mean difference 0.54, CCC=0.82) and depressive symptoms scores (mean difference 0.03, CCC=0.77).Conclusions: We observed that eFHS participants had a high survey return at baseline and each 3-month survey period over the 12 months of follow up. We observed moderate to high agreement between digital and research center measures for several types of surveys, including physical activity, depressive symptoms, and alcohol use. Thus, this digital data collection mechanism is a promising tool to collect data related to cardiovascular disease and its risk factors. [ABSTRACT FROM AUTHOR]

The prediction of arrhythmia recurrences after catheter ablation of atrial fibrillation (AF) remains challenging. The aim of current analysis was to investigate the time-dependent prediction of arrhythmia recurrences after AF catheter ablation during long-term follow-up. The study included 879 patients (61 ± 10 years; 64% males; 39% persistent AF) undergoing first AF catheter ablation. Rhythm outcomes were documented using 7-days Holter monitoring. The APPLE score (Age, Persistent AF, imPaired eGFR, Left atrium (LA), EF) was calculated at baseline, while MB-LATER score (Male gender, Bundle branch block, LA, AF Type, Early Recurrences) 3 months after ablation. The median follow-up time was 37 months [95%CI 35;39]. ERAF and LRAF occurred in 45% and 64%, respectively. On multivariable analysis, ERAF (HR 2.095, 95%CI 1.762–2.490, p < 0.001) was strongly associated with LRAF. The APPLE (HR 1.385, 95%CI 1.276–1.505, p < 0.001) and MB-LATER (HR 1.326, 95%CI 1.239–1.419, p < 0.001) scores significantly predicted LRAF during follow-up. On the ROC analysis, APPLE (AUC 0.640, 95%CI 0.602–0.677, p < 0.001) and MB-LATER (AUC 0.654, 95%CI 0.616–0.691, p < 0.001) demonstrated moderate prediction. Summarizing, ERAF was the strongest predictor for LRAF in time-dependent manner. The APPLE and MB-LATER scores demonstrated moderate prediction of arrhythmia recurrences during long term follow-up. [ABSTRACT FROM AUTHOR]

High-density lipoprotein (HDL), best known for cholesterol transport, also has anti-inflammatory effects. Previous studies suggest involvement of myeloperoxidase (MPO) in modification of HDL. HDL bound Sphingosine-1-phosphate (S1P) has been implied to be an essential protein regarding beneficial HDL effects. In this study, we analyzed anti-inflammatory HDL properties in patients with atrial fibrillation (AF), a disease involving atrial inflammation, compared to non-AF controls and whether anti-inflammatory properties improve upon catheter ablation. Additionally, association with serum concentrations of MPO and S1P were assessed. We isolated HDL from 25 AF patients, 13 non-AF individuals and 14 AF patients at follow-up (FU) after catheter ablation. S1P was measured in a cohort of 141 AF and 21 FU patients. Following preincubation with HDL from either group, bovine aortic endothelial cells were stimulated using tumor necrosis factor α and expression of pro-inflammatory genes intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin (SELE) and P-selectin (SELP) was assessed using qPCR. Concentrations of circulating protein of these genes as well as MPO and S1P were measured in serum samples. Compared to non-AF individuals HDL from AF patients suppressed gene expression of the pro-inflammatory adhesion molecules ICAM1, VCAM1, SELE and SELP 27%, 18%, 21% and 57% less, respectively (p < 0.05 for all except SELE p = 0.06). In FU patients, the anti-inflammatory HDL activity was improved (suppression of ICAM1 + 22%, VCAM1 + 10%, SELE + 38% and SELP + 75%, p < 0.05 for all except VCAM1 p = 0.08). AF patients using angiotensin converting enzyme inhibitors or angiotensin receptor blockers had better anti-inflammatory HDL properties than non-users (gene expression suppression at least 28% more, p < 0.05 for all except ICAM1 p = 0.051). Circulating protein concentrations were not correlated with in vitro gene-expression, but circulating P-selectin was generally elevated in AF and FU patients compared to non-AF patients. MPO plasma concentration was positively associated with gene-expression of ICAM1, VCAM1 and SELP (r2 > 0.4, p < 0.05). Serum concentrations of S1P were increased in FU patients {1.201 µM [1.077–1.543]} compared to AF patients {0.953 µM [0.807–1.135], p < 0.01} but not correlated with ICAM1, VCAM1 and SELP gene expression. We conclude that the anti-inflammatory activity of HDL is impaired in AF patients, which might promote AF progression and AF-associated complications. [ABSTRACT FROM AUTHOR]

Background: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF.Methods: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF.Results: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; P<0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; P<0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF.Conclusions: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time. [ABSTRACT FROM AUTHOR]

Arginine, homoarginine (hArg), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) affect nitric oxide metabolism and altered concentrations are associated with cardiovascular morbidity and mortality. We analyzed these metabolites using liquid chromatography–tandem mass spectrometry in patients with atrial fibrillation (AF) (n = 241) with a focus on heart rhythm at blood withdrawal, AF progression phenotypes, and successful sinus rhythm (SR) restoration (n = 22). AF progression phenotypes were defined as paroxysmal AF with/without low voltage areas (LVA) and persistent AF with/without LVA. While arginine, ADMA, and hArg were within reference limits for healthy controls, SDMA was higher in the AF cohort (0.57 ± 0.12 vs. 0.53 μmol/L (97.5th percentile in reference cohort)). SR restoration in AF patients resulted in normalization of SDMA concentrations (0.465 ± 0.082 vs. 0.570 ± 0.134 μmol/L at baseline, p < 0.001). Patients with AF at the time of blood sampling had significantly lower hArg (1.65 ± 0.51 vs. 1.85 ± 0.60 μmol/L, p = 0.006) and higher ADMA concentrations (0.526 ± 0.08 vs. 0.477 ± 0.08 μmol/L, p < 0.001) compared with AF patients in SR. hArg concentrations were lower in patients with advanced AF progression phenotypes (persistent AF with LVA (p = 0.046)) independent of heart rhythm at blood sampling. Summarizing, arginine metabolism imbalance is associated with AF in general and AF progression and may contribute to associated risk. Key messages: • Heart rhythm at blood withdrawal affects ADMA and hArg level in AF patients. • SDMA is higher in AF patients. • SDMA levels normalize after sinus rhythm restoration. • hArg levels decrease in advanced AF progression phenotypes. [ABSTRACT FROM AUTHOR]

Abstract Introduction Anticoagulantion therapy (OAT) represents the cornerstone to reduce thromboembolic events for atrial fibrillation (AF). Recent studies suggest that AF catheter ablation on top of OAT may be useful to further reduce the thromboembolic risk in AF patients. The aim of the present study is to compare the long-term risk of thromboembolic events and treatment-related complications in patients with AF treated by OAT strategies and catheter ablation. Methods Pubmed, Cochrane and Google Scholar were searched for studies including >500 patients evaluating AF patients treated with OAT (VKA: vitamin K antagonist or DOAC: Direct oral anticoagulants) and/or AF ablation. Pooled incidence of stroke/year was the primary end point, while that of stroke, of all cause bleeding and of major bleeding the secondary ones. All the analyses were stratified according to the CHADS 2 score of included patients. Results Overall, 27 studies were selected, including 50,973 patients in the AF catheter ablation group; 281,595 patients in the VKA group; 54,811 patients in the DOAC group. After a mean follow-up of 2.4 (1.5–3.8) years, the overall incidence of stroke and thromboembolic events was 0.63 per 100 patients/year in AF ablation group, 2.09 per 100 patients/year in VKA group and 1.24 per 100 patients/year in DOAC group (p < 0.001). After stratification in 4 groups according to CHADS 2 score, the incidence of thromboembolic events remained lower in patients included in the AF ablation, followed by DOAC and VKA respectively (p < 0.001), for each CHADS 2 cluster. Both the incidence of all cause bleedings and major bleedings resulted lower in AF ablation group (p < 0.001). The incidence of all-cause mortality in the AF ablation group was significant lower than in the group of OAT (p < 0.0001). Conclusion AF catheter ablation significantly reduces the incidence of long-term thromboembolic events compared to both VKA and DOAC. This reduction is maintained in all CHADS 2 score clusters and is strengthened by the concomitant reduction in hemorrhagic complications provided by AF ablation. Highlights • Anticoagulation therapy (OAT) represents the corner stone to reduce thromboembolic events (TE) for atrial fibrillation (AF). • The aimis to compare the long-term risk of TE in patients with AF treated by OAT and transcatheter ablation. • AF transcatheter ablation significantly reduces the incidence of long-term thromboembolic events compared to both VKA and DOAC. [ABSTRACT FROM AUTHOR]

Background: Individuals with both atrial fibrillation (AF) and myocardial infarction (MI) have higher mortality compared with individuals with only 1 condition. Whether mortality differs according to the temporal order of AF and MI is unclear., Methods and Results: We included participants from the FHS (Framingham Heart Study) from 1960 and onwards. We assessed the hazard ratio (HR) of new-onset AF and MI, and mortality according to MI and AF status (prevalent and interim) using multivariable-adjusted Cox proportional hazards models. Interim diseases were modeled as time-varying variables. For the analysis of new-onset AF, 10 923 participants (55% women; mean±SD age, 54±8 years) were included. For new-onset MI, 10 804 participants (55% women; mean±SD age, 54±8 years) were included. Compared with no MI, the hazard of new-onset AF was higher in participants with prevalent (HR, 1.60 [95% CI, 1.32-1.94]) and interim MI (HR, 3.96 [95% CI, 3.18-4.91]). Both ST-segment-elevation MI and non-ST-segment-elevation MI were associated with new-onset AF. Interim AF, not prevalent AF, was associated with higher hazard rate of new-onset MI (HR, 2.21 [95% CI, 1.67-2.92]). Interim AF was associated with both ST-segment-elevation MI and non-ST-segment-elevation MI. Mortality was significantly greater among participants with AF and MI compared with participants with 1 of the 2, regardless of temporal order., Conclusions: We report a bidirectional association between AF and MI, which was observed for both non-ST-segment-elevation MI and ST-segment-elevation MI. Participants with both AF and MI had considerably higher mortality compared with participants with only 1 of the 2 conditions, regardless of order.

Background: Disorders affecting cardiac conduction are associated with substantial morbidity. Understanding the epidemiology and risk factors for conduction disorders may enable earlier diagnosis and preventive efforts., Objectives: The purpose of this study was to quantify contemporary frequency and risk factors for electrocardiogram (ECG)-defined cardiac conduction disorders in a large multi-institutional primary care sample., Methods: We quantified prevalence and incidence of conduction disorders among adults receiving longitudinal primary care between 2001 and 2019, each with at least one 12-lead ECG performed prior to the start of follow-up and at least one ECG during follow-up. We defined conduction disorders using curated terms extracted from ECG diagnostic statements by cardiologists. We grouped conduction disorders by inferred anatomic location of abnormal conduction. We tested associations between clinical factors and incident conduction disease using multivariable proportional hazards regression., Results: We analyzed 189,163 individuals (median age 55 years; 58% female). The overall prevalence of conduction disorders was 27% among men and 15% among women. Among 119,926 individuals (median age 55 years; 51% female), 6,802 developed an incident conduction system abnormality over a median of 10 years (Q1, Q3: 6, 15 years) of follow-up. Incident conduction disorders were more common in men (8.78 events/1,000 person-years) vs women (4.34 events/1,000 person-years, P  < 0.05). In multivariable models, clinical factors including older age (HR: 1.25 per 5-year increase [95% CI: 1.24-1.26]) and myocardial infarction (HR: 1.39 [95% CI: 1.26-1.54]) were associated with incident conduction disorders., Conclusions: Cardiac conduction disorders are common in a primary care population, especially among older individuals with cardiovascular risk factors., Competing Interests: Dr Lubitz is a full-time employee of Novartis as of July 2022. He received sponsored research support from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Fitbit, Medtronic, Premier, and IBM, and has consulted for Bristol Myers Squibb, Pfizer, Blackstone Life Sciences, and Invitae. Dr Ellinor receives sponsored research support from Bayer AG and IBM and has consulted for Novartis, MyoKardia, and Bayer AG. Dr Ho has received sponsored research support from Bayer AG. Dr Batra receives sponsored research support from Bayer AG and IBM and has consulted for Novartis and Prometheus Biosciences. Dr Philippakis is a Venture Partners and employee at GV, has consulted for Novartis and Rakuten, and receives sponsored research support from Verily, Microsoft, IBM, Intel, Pfizer, Abbvie, Biogen, Ionnis and Bayer. Investigators were supported by 10.13039/100000002National Institutes of Health grants K23HL169839-01 (Dr Khurshid), R38HL150212 (Dr Haimovich); R01HL139731 (Dr Lubitz), R01HL157635 (Dr Lubitz), R01HL134893 (Dr Ho), R01HL140224 (Dr Ho), K24HL153669 (Dr Ho), 2R01HL092577 (Dr Ellinor), and 1R01AG066010, R01HL092577 (Dr Benjamin); 10.13039/100000968American Heart Association grants 18SFRN34250007 (Dr Lubitz), AF 18SFRN34110082 (Dr Benjamin), 2023CDA1050571 (Dr Khurshid) and 18SFRN34110082 (Dr Ellinor); and by a grant from the European Union, MAESTRIA 965286 (Dr Ellinor). Dr Kornej has received funding from the 10.13039/100018694Marie Sklodowska-Curie Actions under the European Union’s 10.13039/100010661Horizon 2020 research and innovation programme (Agreement No 838259). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Atrial fibrillation (AF) is associated with an increased risk of myocardial infarction (MI) and vice versa. This bidirectional association relies on shared risk factors as well as on several direct and indirect mechanisms, including inflammation, atrial ischaemia, left ventricular remodelling, myocardial oxygen supply-demand mismatch and coronary artery embolism, through which one condition can predispose to the other. Patients with both AF and MI are at greater risk of stroke, heart failure and death than patients with only one of the conditions. In this Review, we describe the bidirectional association between AF and MI. We discuss the pathogenic basis of this bidirectional relationship, describe the risk of adverse outcomes when the two conditions coexist, and review current data and guidelines on the prevention and management of both conditions. We also identify important gaps in the literature and propose directions for future research on the bidirectional association between AF and MI. The Review also features a summary of methodological approaches for the study of bidirectional associations in population-based studies., (© 2023. Springer Nature Limited.)

Background: Deep neural networks have been used to estimate age from ECGs, the electrocardiographic age (ECG-age), which predicts adverse outcomes. However, this prediction ability has been restricted to clinical settings or relatively short periods. We hypothesized that ECG-age is associated with death and cardiovascular outcomes in the long-standing community-based FHS (Framingham Heart Study)., Methods: We tested the association of ECG-age with chronological age in the FHS cohorts in ECGs from 1986 to 2021. We calculated the gap between chronological and ECG-age (Δage) and classified individuals as having normal, accelerated, or decelerated aging, if Δage was within, higher, or lower than the mean absolute error of the model, respectively. We assessed the associations of Δage, accelerated and decelerated aging with death or cardiovascular outcomes (atrial fibrillation, myocardial infarction, and heart failure) using Cox proportional hazards models adjusted for age, sex, and clinical factors., Results: The study population included 9877 FHS participants (mean age, 55±13 years; 54.9% women) with 34 948 ECGs. ECG-age was correlated to chronological age (r=0.81; mean absolute error, 9±7 years). After 17±8 years of follow-up, every 10-year increase of Δage was associated with 18% increase in all-cause mortality (hazard ratio [HR], 1.18 [95% CI, 1.12-1.23]), 23% increase in atrial fibrillation risk (HR, 1.23 [95% CI, 1.17-1.29]), 14% increase in myocardial infarction risk (HR, 1.14 [95% CI, 1.05-1.23]), and 40% increase in heart failure risk (HR, 1.40 [95% CI, 1.30-1.52]), in multivariable models. In addition, accelerated aging was associated with a 28% increase in all-cause mortality (HR, 1.28 [95% CI, 1.14-1.45]), whereas decelerated aging was associated with a 16% decrease (HR, 0.84 [95% CI, 0.74-0.95])., Conclusions: ECG-age was highly correlated with chronological age in FHS. The difference between ECG-age and chronological age was associated with death, myocardial infarction, atrial fibrillation, and heart failure. Given the wide availability and low cost of ECG, ECG-age could be a scalable biomarker of cardiovascular risk., Competing Interests: Disclosures None.

Background: Physical inactivity is a known risk factor for atrial fibrillation (AF). Wearable devices, such as smartwatches, present an opportunity to investigate the relation between daily step count and AF risk., Objective: The objective of this study was to investigate the association between daily step count and the predicted 5-year risk of AF., Methods: Participants from the electronic Framingham Heart Study used an Apple smartwatch. Individuals with diagnosed AF were excluded. Daily step count, watch wear time (hours and days), and self-reported physical activity data were collected. Individuals' 5-year risk of AF was estimated, using the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)-AF score. The relation between daily step count and predicted 5-year AF risk was examined via linear regression, adjusting for age, sex, and wear time. Secondary analyses examined effect modification by sex and obesity (BMI≥30 kg/m 2 ), as well as the relation between self-reported physical activity and predicted 5-year AF risk., Results: We examined 923 electronic Framingham Heart Study participants (age: mean 53, SD 9 years; female: n=563, 61%) who had a median daily step count of 7227 (IQR 5699-8970). Most participants (n=823, 89.2%) had a <2.5% CHARGE-AF risk. Every 1000 steps were associated with a 0.08% lower CHARGE-AF risk (P<.001). A stronger association was observed in men and individuals with obesity. In contrast, self-reported physical activity was not associated with CHARGE-AF risk., Conclusions: Higher daily step counts were associated with a lower predicted 5-year risk of AF, and this relation was stronger in men and participants with obesity. The utility of a wearable daily step counter for AF risk reduction merits further investigation., (©Ayelet Shapira-Daniels, Jelena Kornej, Nicole L Spartano, Xuzhi Wang, Yuankai Zhang, Chathurangi H Pathiravasan, Chunyu Liu, Ludovic Trinquart, Belinda Borrelli, David D McManus, Joanne M Murabito, Emelia J Benjamin, Honghuang Lin. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 06.03.2023.)

Chronic inflammation is a continuous low-grade activation of the systemic immune response. Whereas downstream inflammatory markers are associated with atrial fibrillation (AF), upstream inflammatory effectors including eicosanoids are less studied. To examine the association between eicosanoids and incident AF. We used a liquid chromatography-mass spectrometry for the non-targeted measurement of 161 eicosanoids and eicosanoid-related metabolites in the Framingham Heart Study. The association of each eicosanoid and incident AF was assessed using Cox proportional hazards models and adjusted for AF risk factors, including age, sex, height, weight, systolic/diastolic blood pressure, current smoking, antihypertensive medication, diabetes, history of myocardial infarction and heart failure. False discovery rate (FDR) was used to adjust for multiple testing. Eicosanoids with FDR < 0.05 were considered significant. In total, 2676 AF-free individuals (mean age 66 ± 9 years, 56% females) were followed for mean 10.8 ± 3.4 years; 351 participants developed incident AF. Six eicosanoids were associated with incident AF after adjusting for multiple testing (FDR < 0.05). A joint score was built from the top eicosanoids weighted by their effect sizes, which was associated with incident AF (HR = 2.72, CI = 1.71-4.31, P = 2.1 × 10 -5 ). In conclusion, six eicosanoids were associated with incident AF after adjusting for clinical risk factors for AF., (© 2022. The Author(s).)

Background: The heartbeat-evoked potential (HEP) is a brain response to each heartbeat, which is thought to reflect cardiac signaling to central autonomic areas and suggested to be a marker of internal body awareness (eg, interoception)., Objectives: Because cardiac communication with central autonomic circuits has been shown to be impaired in patients with atrial fibrillation (AF), we hypothesized that HEPs are attenuated in these patients., Methods: By simultaneous electroencephalography and electrocardiography recordings, HEP was investigated in 56 individuals with persistent AF and 56 control subjects matched for age, sex, and body mass index., Results: HEP in control subjects was characterized by right frontotemporal negativity peaking around 300 to 550 ms after the R-peak, consistent with previous studies. In comparison with control subjects, HEP amplitudes were attenuated, and HEP amplitude differences remained significant when matching the samples for heart frequency, stroke volume (assessed by echocardiography), systolic blood pressure, and the amplitude of the T-wave. Effect sizes for the group differences were medium to large (Cohen's d between 0.6 and 0.9). EEG source analysis on HEP amplitude differences pointed to a neural representation within the right insular cortex, an area known as a hub for central autonomic control., Conclusions: The heartbeat-evoked potential is reduced in AF, particularly in the right insula. We speculate that the attenuated HEP in AF may be a marker of impaired heart-brain interactions. Attenuated interoception might furthermore underlie the frequent occurrence of silent AF., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Social isolation might be considered as a marker of poor health and higher mortality. The aim of our analysis was to assess the association of social network index (SNI) with incident AF and death. We selected participants aged ≥ 55 years without prevalent AF from the Framingham Heart Study. We evaluated the association between social isolation measured by the Berkman-Syme Social Network Index (SNI), incident AF, and mortality without diagnosed AF. We assessed the risk factor-adjusted associations between SNI (the sum of 4 components: marriage status, close friends/relatives, religious service attendance, social group participation), incident AF, and mortality without AF by using Fine-Gray competing risk regression models. We secondarily examined the outcome of all-cause mortality. We included 3454 participants (mean age 67 ± 10 years, 58% female). During 11.8 ± 5.2 mean years of follow-up, there were 686 incident AF cases and 965 mortality without AF events. Individuals with fewer connections had lower rates of incident AF (P = 0.04) but higher rates of mortality without AF (P = 0.03). Among SNI components, only social group participation was associated with higher incident AF (subdistribution hazards ratio [sHR] 1.35, 95% CI 1.16-1.57, P = 0.0001). For mortality without AF, social group participation (sHR = 0.81, 95% CI 0.71-0.93, P = 0.002) and regular religious service attendance sHR = 0.76, 95% CI 0.67-0.87, P < 0.0001) were associated with lower risk of death. Social isolation was associated with a higher rate of mortality without diagnosed AF. In contrast to our hypothesis, we observed that poor social connectedness was associated with a lower rate of incident AF. This finding should be interpreted cautiously since there were very few participants in the lowest social connectedness group. Additionally, the seemingly protective effect of social isolation on AF incidence may be simply an artifact of the strong association between social isolation and increased mortality rate in combination with the large number of deaths as compared to AF events in our study. Further study is warranted., (© 2022. The Author(s).)

Background: Recent studies have reported an association between N-terminal atrial natriuretic peptide (NT-proANP) and the progression of atrial fibrillation (AF). However, NT-proANP levels in peripheral and cardiac circulation in AF patients and in non-AF individuals need to be defined. The aims of the current study are (1) to analyze NT-proANP levels in peripheral and cardiac circulation in AF patients and (2) to compare NT-proANP levels in individuals with and without AF., Methods: We recruited AF patients who were undergoing their first AF catheter ablation and non-AF individuals. Blood plasma samples taken from the femoral vein and the left atrium (LA) were collected before AF ablation in the AF patients and from the cubital vein in the non-AF controls. Low voltage areas (LVAs) were determined using high-density maps during catheter ablation and defined as < 0.5 mV., Results: The study included 189 AF patients (64 ± 10 years, 59% male, 61% persistent AF, 30% LVAs) and 26 non-AF individuals (58 ± 10 years, 50% male). Patients with AF were significantly older and had larger LA (p < 0.05). Compared to non-AF controls, peripheral and cardiac NT-proANP levels were significantly higher in AF patients without and with LVAs (median 5.4, 10.5, 14.8 ng/ml, respectively, p < 0.001). In multivariable analysis, NT-proANP (OR 1.238, 95% CI 1.007-1.521, p = 0.043) remained significantly different between non-AF individuals and AF patients. In AF, NT-proANP levels were significantly higher in the cardiac blood samples than in the peripheral blood (median 13.0 versus 11.4 ng/ml, p = 0.003). The ability to predict LVAs was modest when using cardiac NT-proANP (AUC 0.661) and peripheral NT-proANP (AUC 0.635), without statistical difference (p = 0.937)., Conclusions: NT-proANP levels are higher in individuals with AF than in controls and are more pronounced in progressed AF. Elevated cardiac and peripheral NT-proANP levels similarly predict LVAs., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Atrial fibrillation affects almost 60 million adults worldwide. Atrial fibrillation is associated with a high risk of cardiovascular morbidity and death as well as with social, psychological and economic burdens on patients and their families. Social determinants - such as race and ethnicity, financial resources, social support, access to health care, rurality and residential environment, local language proficiency and health literacy - have prominent roles in the evaluation, treatment and management of atrial fibrillation. Addressing the social determinants of health provides a crucial opportunity to reduce the substantial clinical and non-clinical complications associated with atrial fibrillation. In this Review, we summarize the contributions of social determinants to the patient experience and outcomes associated with this common condition. We emphasize the relevance of social determinants and their important intersection with atrial fibrillation treatment and outcomes. In closing, we identify gaps in the literature and propose future directions for the investigation of social determinants and atrial fibrillation., (© 2021. Springer Nature Limited.)

Aims: Heart failure with preserved ejection fraction (HFpEF) is a rapidly growing global health problem. To date, diagnosis of HFpEF is based on clinical, invasive, and laboratory examinations. Electrocardiographic findings may vary, and there are no known typical ECG features for HFpEF., Methods and Results: This study included two patient cohorts. In the derivation cohort, we included n  = 1884 patients who presented with exertional dyspnoea or equivalent and preserved ejection fraction (≥50%) and clinical suspicion for coronary artery disease. The ECGs were divided in segments, yielding a total of 77 558 samples. We trained a convolutional neural network (CNN) to classify HFpEF and control patients according to European Society of Cardiology (ESC) criteria. An external group of 203 volunteers in a prospective heart failure screening programme served as a validation cohort of the CNN. The external validation of the CNN yielded an area under the curve of 0.80 [95% confidence interval (CI) 0.74-0.86] for detection of HFpEF according to ESC criteria, with a sensitivity of 0.99 (95% CI 0.98-0.99) and a specificity of 0.60 (95% CI 0.56-0.64), with a positive predictive value of 0.68 (95%CI 0.64-0.72) and a negative predictive value of 0.98 (95% CI 0.95-0.99)., Conclusion: In this study, we report the first deep learning-enabled CNN for identifying patients with HFpEF according to ESC criteria including NT-proBNP measurements in the diagnostic algorithm among patients at risk. The suitability of the CNN was validated on an external validation cohort of patients at risk for developing heart failure, showing a convincing screening performance., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: P-wave signal-averaged electrocardiography (P-SAECG) quantifies atrial electrical activity. P-SAECG measures and their clinical correlates and heritability have had limited characterization in community-based cohorts., Objective: The purpose of this study was to (1) establish reference values; (2) identify clinical risk factors associated with P-SAECG; and (3) estimate genetic heritability for P-SAECG traits., Methods: We performed P-SAECG in 2 generations of Framingham Heart Study participants. We performed backward elimination regression models to assess associations of clinical factors with each SAECG trait (P-wave [PW] duration, root mean square voltage in terminal 40 ms [RMS40], terminal 30 ms RMS30, terminal 20 ms RMS20, RMS PW, and PW integral). We estimated the adjusted genetic heritability of P-SAECG measures using the Sequential Oligogenic Linkage Analysis Routines (SOLAR) program., Results: We included 4307 participants (age 55 ± 14 years; 56% female). The reference values were derived from 1752 participants without cardiovascular risk factors. Median (2.5th percentile; 97.5th percentile) total PW duration was 118 ms (93; 146) in women and 128 ms (104; 158) in men in the reference sample, and 121 ms (94; 151) in women and 129 ms (103; 159) in the entire study cohort (broad sample). In the broad sample, after adjusting for age and sex, total PW duration was positively associated with height, weight, prevalent heart failure, history of atrial fibrillation (AF), and atrioventricular node blockers, and negatively associated with smoking, waist circumference, heart rate, and diabetes. The estimated heritability of P-SAECG traits was moderate, ranging from 11.9% for RMS30 to 24.9% for PW integral., Conclusion: P-SAECG traits are associated with multiple AF-related risk factors and are moderately heritable., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood., Methods: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval)., Results: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes ( KCNQ1 , KCNH2 , and SCN5A ), a controversial monogenic SCD gene ( KCNE1 ), and novel genes ( PAM and MFGE8 ) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block ( P =8.4×10 -5 ). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation ( P =4×10 -25 ), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals., Conclusions: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

Background: All-cause mortality following atrial fibrillation (AF) has decreased over time. Data regarding temporal trends in causes of death among individuals with AF are scarce. The aim of our study was to analyze temporal trends in cause-specific mortality and predictors for cardiovascular (CVD) and non-CVD deaths among participants with incident AF in the Framingham Heart Study., Methods: We categorized all newly diagnosed AF cases according to age at AF diagnosis (< 70, 70 to < 80, and ≥ 80 years) and epoch of AF diagnosis (< 1990, 1990-2002, and ≥ 2003). We followed participants until death or the last follow-up. We categorized death causes into CVD, non-CVD, and unknown causes. For each age group, we tested for trends in the cumulative incidence of cause-specific death across epochs. We fit multivariable Fine-Gray models to assess subdistribution hazard ratios (HR) between clinical risk factors at AF diagnosis and cause-specific mortality., Results: We included 2125 newly diagnosed AF cases (mean age 75.5 years, 47.8% women). During a median follow-up of 4.8 years, 1657 individuals with AF died. There was evidence of decreasing CVD mortality among AF cases diagnosed < 70 years and 70 to < 80 years (p trend < 0.001) but not ≥ 80 years (p = 0.76). Among the cases diagnosed < 70 years, the cumulative incidence of CVD death at 75 years was 67.7% in epoch 1 and 13.9% in epoch 3; among those 70 to < 80 years, the incidence at 85 years was 58.9% in epoch 1 and 18.9% in epoch 3. Advancing age (HR per 1 SD increase 6.33, 95% CI 5.44 to 7.37), prior heart failure (HR 1.49, 95% CI 1.14-1.94), and prior myocardial infarction (HR 1.44, 95% CI 1.15-1.80) were associated with increased rate of CVD death., Conclusions: In this community-based cohort, CVD mortality among AF cases decreased over time. Most deaths in individuals with AF are no longer CVD-related, regardless of age at AF diagnosis., (© 2021. The Author(s).)

Aims: The presence of low-voltage areas (LVAs) in patients with atrial fibrillation (AF) reflects left atrial (LA) electroanatomical substrate, which is essential for individualized AF management. However, echocardiographic anteroposterior LA diameter included into previous LVAs prediction scores does not mirror LA size accurately and impaired left ventricular ejection fraction (LV-EF) is not directly associated with atrial myopathy. Therefore, we aimed to compare a modified (m)APPLE score, which included LA volume (LAV) and LA emptying fraction (LA-EF) with the regular APPLE score for the prediction of LVAs., Methods and Results: In patients undergoing first AF catheter ablation, LVAs were determined peri-interventionally using high-density maps and defined as signal amplitude <0.5 mV. All patients underwent cardiovascular magnetic resonance imaging before intervention. The APPLE (one point for Age ≥ 65 years, Persistent AF, imPaired eGFR ≤ 60 mL/min/1.73 m2, LA diameter ≥ 43 mm, and LVEF < 50%) and (m)APPLE (last two variables changed by LAV ≥ 39 mL/m2, and LA-EF < 31%) scores were calculated at baseline. The study population included 219 patients [median age 65 (interquartile range 57-72) years, 41% females, 59% persistent AF, 25% LVAs]. Both scores were significantly associated with LVAs [OR 1.817, 95% CI 1.376-2.399 for APPLE and 2.288, 95% CI 1.650-3.172 for (m)APPLE]. Using receiver operating characteristic curves analysis, the (m)APPLE score [area under the curve (AUC) 0.779, 95% CI 0.702-0.855] showed better LVAs prediction than the APPLE score (AUC 0.704, 95% CI 0.623-0.784), however, without statistically significant difference (P = 0.233)., Conclusion: The modified (m)APPLE score demonstrated good prognostic value for LVAs prediction and was comparable with the regular APPLE score., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Rationale: A sedentary lifestyle is associated with increased risk for cardiovascular disease (CVD). Smartwatches enable accurate daily activity monitoring for physical activity measurement and intervention. Few studies, however, have examined physical activity measures from smartwatches in relation to traditional risk factors associated with future risk for CVD., Objective: To investigate the association of habitual physical activity measured by smartwatch with predicted CVD risk in adults., Methods and Results: We enrolled consenting FHS (Framingham Heart Study) participants in an ongoing eFHS (electronic Framingham Heart Study) at the time of their FHS research center examination. We provided participants with a smartwatch (Apple Watch Series 0) and instructed them to wear it daily, which measured their habitual physical activity as the average daily step count. We estimated the 10-year predicted risk of CVD using the American College of Cardiology/American Heart Association 2013 pooled cohort risk equation. We estimated the association between physical activity and predicted risk of CVD using linear mixed effects models adjusting for age, sex, wear time, and familial structure. Our study included 903 eFHS participants (mean age 53±9 years, 61% women, 9% non-White) who wore the smartwatch ≥5 hours per day for ≥30 days. Median daily step count was similar among men (7202 with interquartile range 3619) and women (7260 with interquartile range 3068; P =0.52). Average 10-year predicted CVD risk was 4.5% (interquartile range, 6.1%) for men and 1.2% (interquartile range, 2.2%) for women ( P =1.3×10 -26 ). Every 1000 steps higher habitual physical activity was associated with 0.18% lower predicted CVD risk ( P =3.2×10 -4 ). The association was attenuated but remained significant after further adjustment for body mass index ( P =0.01)., Conclusions: In this community-based sample of adults, higher daily physical activity measured by a study smartwatch was associated with lower predicted risk of CVD. Future research should examine the longitudinal association of prospectively measured daily activity and incident CVD.

Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD., Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies., Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci ( TTN , CAND2 , SCN10A , PITX2 , CAV1 , SYNPO2L , SOX5 , TBX5, MYH6, RPL3L ). The top variants at known sarcomere genes ( TTN, MYH6 ) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A ) were associated with longer PWD but lower AF risk., Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

Objectives: The prognostic value of biomarkers in aortic stenosis (AS) remains understudied. We investigated whether a combination of biomarkers related to cardiovascular stress, inflammation, and damage is associated with mortality in patients with severe AS undergoing surgical aortic valve replacement (SAVR)., Methods: From a prospective registry of patients with severe AS referred for SAVR, 499 participants (mean age, 68 ± 8.5 years; 292 male) with available preoperative echocardiograms and biomarker data were included. Preoperative concentrations of NT-pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, and C-reactive protein were dichotomized as high or low, according to calculated cut-off values., Results: The mean follow-up time was 775 ± 410 days; 25 patients died. Only patients with elevated levels of all three biomarkers (n = 55) showed increased mortality [hazard ratio (HR), 7.26; 95% confidence interval (CI), 2.52-20.93; p < 0.001; reference group, no elevated biomarkers, n = 159]. Patients with elevated levels of the three biomarkers had higher 3-year all-cause mortality (24% vs. 4.5%); this remained true after multivariable adjustment (HR, 4.08; 95% CI, 1.87-8.87; p < 0.001). Patients with EuroSCOREs (logES) >3.0% tended to exhibit a higher risk of all-cause mortality (HR, 2.19; 95% CI, 0.98-4.87; p = 0.055); the mortality rate was 12-fold higher when logES >3 was combined with the three elevated biomarkers. This combination also showed a net reclassification improvement of 33% and significant likelihood-ratio test results., Conclusions: A multiple biomarker approach might be useful for predicting postoperative mid-term mortality in patients with severe AS undergoing SAVR. Further large-scale prospective validation should be performed., (Copyright © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)