The NORwegian atrial fibrillation self-SCREENing (NORSCREEN) trial: rationale and design of a randomized controlled trial.

AIMS: Atrial fibrillation (AF) is a common arrhythmia, and many cases of AF may be undiagnosed. Whether screening for AF and subsequent treatment if AF is detected can improve long-term outcome remains an unsettled question. The primary aim of the NORwegian atrial fibrillation self-SCREENing (NORSCREEN) trial is to assess whether self-screening for AF with continuous electrocardiogram (ECG) for 3-7 days in individuals aged 65 years or older with at least one additional risk factor for stroke, and initiation of guideline-recommended therapy in patients with detected AF, will reduce the occurrence of stroke. METHODS AND RESULTS: This study is a nationwide open, siteless, randomized, controlled trial. Individuals ≥65 years of age are randomly identified from the National Population Register of Norway and are invited to take a digital inclusion/exclusion test. Individuals passing the inclusion/exclusion test are randomized to either the intervention group or the control group. A total of 35 000 participants will be enrolled. In the intervention group, self-screening is performed continuously over 3-7 days at home with a patch ECG device (ECG247) at inclusion and after 12-18 months. If AF is detected, guideline-recommended therapy will be initiated. Patients will be followed up for 5 years through national health registries. The primary outcome is time to a first stroke (ischaemic or haemorrhagic stroke). The first participant in the NORSCREEN trial was enrolled on 1 September 2023. CONCLUSION: The results from the NORSCREEN trial will provide new insights regarding the efficacy of digital siteless self-screening for AF with respect to stroke prevention in individuals at an increased risk of stroke. TRIAL REGISTRATION: Clinical trials: NCT05914883.

Thawing plateau time indicating the duration of phase transition from ice to water is the strongest predictor for long-term durable pulmonary vein isolation after cryoballoon ablation for atrial fibrillation-Data from the index and repeat procedures.

Introduction: This study aimed to clarify the relationship between the durability of pulmonary vein (PV) isolation and the time of phase transition from ice to water indicated by thawing plateau time in a cryoballoon ablation for atrial fibrillation (AF). Methods and results: In this retrospective study, 241 PVs from 71 patients who underwent a repeat AF ablation 526 (IQR: 412, 675) days after a cryoballoon ablation were analyzed. Reconnection was observed in 101 (41.9%) PVs of 53 patients (74.6%). Thawing plateau time (TimeTP) was defined as the time from 0°C to 10°C inside the balloon in the thawing period. Durable PV isolation was associated with significantly longer TimeTP compared with PV reconnection (26.0 vs. 11.0 s, P < 0.001). The proportion of durable PV isolations increased with TimeTP in a dose-proportional manner. The cut point for PV reconnection was TimeTP <15 s with a positive predictive value of 82.1% (sensitivity = 63.4%, specificity = 90.0%) while for durable PV isolation the cut point was TimeTP >25 s with a positive predictive value of 84.6% (sensitivity = 55.0%, specificity = 86.1%). In the analysis of multivariable logistic regression, location of PV reconnection (P < 0.01), TimeTP (P < 0.05) and thawing plateau integral (P < 0.01) were shown as independent predictors for durable PV isolation. Conclusion: TimeTP is an independent predictor for the durability of PV isolation, and it presents in a dose-proportional manner. TimeTP <15 s predicts long-term reconnection while TimeTP >25 s predicts durable PV isolation.

Virus Evolution on Fitness Landscapes.

The landscape paradigm is revisited in the light of evolution in simple systems. A brief overview of different classes of fitness landscapes is followed by a more detailed discussion of the RNA model, which is currently the only evolutionary model that allows for a comprehensive molecular analysis of a fitness landscape. Neutral networks of genotypes are indispensable for the success of evolution. Important insights into the evolutionary mechanism are gained by considering the topology of sequence and shape spaces. The dynamic concept of molecular quasispecies is viewed in the light of the landscape paradigm. The distribution of fitness values in state space is mirrored by the population structures of mutant distributions. Two classes of thresholds for replication error or mutations are important: (i) the-conventional-genotypic error threshold, which separates ordered replication from random drift on neutral networks, and (ii) a phenotypic error threshold above which the molecular phenotype is lost. Empirical landscapes are reviewed and finally, the implications of the landscape concept for virus evolution are discussed.

Cryoballoon vs. radiofrequency catheter ablation: insights from NOrwegian randomized study of PERSistent Atrial Fibrillation (NO-PERSAF study).

AIMS: Pulmonary vein isolation (PVI) is still regarded as a cornerstone for treatment of persistent atrial fibrillation (AF). This study evaluated the effectiveness of PVI performed with cryoballoon ablation (CBA) in comparison with radiofrequency ablation (RFA) in patients with persistent AF. METHODS AND RESULTS: A total of 101 patients with symptomatic persistent AF were enrolled and randomized (1:1) to CBA or RFA groups and followed up for 12 months. The primary endpoint was any documented recurrent atrial tachyarrhythmia (ATA) lasting longer than 30 s following a 3-month blanking period. Secondary endpoints were procedure-related complications, procedure and ablation duration, and fluoroscopy time. The ATA-free survival curves were estimated by Kaplan-Meier method and analysed by the log-rank test. According to intention-to-treat analysis, freedom from ATA was achieved in 36 out of 52 patients in the CBA group and 30 out of 49 patients in the RFA group (69.2% vs. 61.2%, P = 0.393). No difference in AF recurrence was found between the two groups (27.5% in CBA vs. 38.0% in RFA, P = 0.258), and less atrial flutter recurrence was documented in the CBA group compared with the RFA group (3.9% vs. 18.0%, P = 0.020). The procedure and ablation duration were significantly shorter in the CBA group (160 ± 31 vs. 197 ± 38 min, P < 0.0001; 36.7 ± 9.5 vs. 55.3 ± 16.7 min, P < 0.0001). There was no difference regarding fluoroscopy time (21.5 ± 7.8 vs. 23.4 ± 11.2 min, P > 0.05). CONCLUSION: Compared with RFA, PVI performed by CBA led to shorter procedure and ablation duration, with less atrial flutter recurrence and similar freedom from ATA at 12-month follow-up.

The impacts of contact force, power and application time on ablation effect indicated by serial measurements of impedance drop in both conventional and high-power short-duration ablation settings of atrial fibrillation.

BACKGROUND: This study aimed to clarify the interrelationship and additive effects of contact force (CF), power and application time in both conventional and high-power short-duration (HPSD) settings. METHODS: Among 38 patients with paroxysmal atrial fibrillation who underwent first-time pulmonary vein isolation, 787 ablation points were collected at the beginning of the procedure at separate sites. Energy was applied for 60 s under power outputs of 25, 30 or 35 W (conventional group), or 10 s when using 50 W (HPSD group). An impedance drop (ID) of 10 Ω was regarded as a marker of adequate lesion formation. RESULTS: ID ≥ 10 Ω could not be achieved with CF < 5 g under any power setting. With CF ≥ 5 g, ID could be enhanced by increasing power output or prolonging ablation time. ID for 30 and 35 W was greater than for 25 W (p < 0.05). Ablation with 35 W resulted in greater ID than with 30 W only when CF of 10-20 g was applied for 20-40 s (p < 0.05). Under the same power output, ID increased with CF level at different time points. The higher the CF, the shorter the time needed to reach ID of 10 Ω and maximal ID. ID correlated well with ablation index under each power, except for lower ID values at 25 W. ID with 50 W for 10 s was equivalent to that with 25 W for 40 s, but lower than that with 30 W for 40 s or 35 W for 30 s. CONCLUSIONS: CF of at least 5 g is required for adequate ablation effect. With CF ≥ 5g, CF, power output, and ablation time can compensate for each other. Time to reach maximal ablation effect can be shortened by increasing CF or power. The effect of HPSD ablation with 50 W for 10 s is equivalent to conventional ablation with 25 W for 40 s and 30-35 W for 20-30 s in terms of ID.

Short and long-term effects of single and multiple sessions of electroconvulsive therapy on brain gray matter volumes.

BACKGROUND: Electroconvulsive therapy (ECT) has been shown to induce broadly distributed cortical and subcortical volume increases, more prominently in the amygdala and the hippocampus. Structural changes after one ECT session and in the long-term have been understudied. OBJECTIVE: The aim of this study was to describe short-term and long-term volume changes induced in cortical and subcortical regions by ECT. METHODS: Structural brain data were acquired from depressed patients before and 2 h after their first ECT session, 7-14 days after the end of the ECT series and at 6 months follow up (N = 34). Healthy, age and gender matched volunteers were scanned according to the same schedule (N = 18) and patients affected by atrial fibrillation were scanned 1-2 h before and after undergoing electrical cardioversion (N = 16). Images were parcelled using FreeSurfer and estimates of cortical gray matter volume and subcortical volume changes were obtained using Quarc. RESULTS: Volume increase was observable in most of gray matter regions after 2 h from the first ECT session, with significant results in brain stem, bilateral hippocampi, right putamen and left thalamus, temporal and occipital regions in the right hemisphere. At the end of treatment series, widespread significant volume changes were observed. After six months, the right amygdala volume was still significantly increased. No significant changes were observed in the comparison groups. CONCLUSIONS: Volume increases in gray matter areas can be detected 2 h after a single ECT session. Further studies are warranted to explore the underlying molecular mechanisms.

Performance of an active fixation bipolar left ventricular lead vs passive fixation quadripolar leads in cardiac resynchronization therapy, a randomized trial.

BACKGROUND: Usage of active fixation bipolar left ventricular (LV) leads represents an alternative approach to the more commonly used passive fixation quadripolar leads in cardiac resynchronization therapy (CRT). We compared a bipolar LV lead with a side screw for active fixation and passive fixation quadripolar LV leads. METHODS: Sixty-two patients were before CRT implantations randomly allocated to receive a bipolar (n = 31) or quadripolar (n = 31) LV leads. Speckle-tracking radial strain echocardiography was used to define the LV segment with latest mechanical activation as the target LV segment. The electrophysiological measurements and the capability to obtain a proximal position in a coronary vein placed over the target segment were assessed. RESULTS: Upon implantation, the quadripolar lead demonstrated a lower pacing capture threshold than the bipolar lead, but at follow-up, there was no difference. There were no differences in the LV lead implant times or radiation doses. The success rate in reaching the target location was not significantly different between the two LV leads. CONCLUSIONS: The pacing capture thresholds were low, with no significant difference between active fixation bipolar leads and quadripolar leads. Active fixation leads did not promote a more proximal location of the stimulating electrode or a higher grade of concordance to the target segment than passive fixation leads.

Comparable Long-Term Rabies Immunity in Foxes after IntraMuscular and Oral Application Using a Third-Generation Oral Rabies Virus Vaccine.

The live genetically-engineered oral rabies virus (RABV) variant SPBN GASGAS induces long-lasting immunity in foxes and protection against challenge with an otherwise lethal dose of RABV field strains both after experimental oral and parenteral routes of administration. Induction of RABV-specific binding antibodies and immunoglobulin isotypes (IgM, total IgG, IgG1, IgG2) were comparable in orally and parenterally vaccinated foxes. Differences were only observed in the induction of virus-neutralizing (VNA) titers, which were significantly higher in the parenterally vaccinated group. The dynamics of rabies-specific antibodies pre- and post-challenge (365 days post vaccination) suggest the predominance of type-1 immunity protection of SPBN GASGAS. Independent of the route of administration, in the absence of IgG1 the immune response to SPBN GAGAS was mainly IgG2 driven. Interestingly, vaccination with SPBN GASGAS does not cause significant differences in inducible IFN-γ production in vaccinated animals, indicating a relatively weak cellular immune response during challenge. Notably, the parenteral application of SPBN GASGAS did not induce any adverse side effects in foxes, thus supporting safety studies of this oral rabies vaccine in various species.

Clinical outcome of cardiac resynchronization therapy in patients randomized to an active fixation bipolar left ventricular lead versus a passive quadripolar lead.

Objectives: To compare the clinical outcome of cardiac resynchronization therapy (CRT) in patients receiving a bipolar left ventricular (LV) lead with a side helix for active fixation to the outcome in patients receiving a quadripolar passive fixation LV lead.Design: Sixty-two patients (mean age 72 ± 11 years) were blindly and randomly assigned to the active fixation bipolar lead group (n = 31) or to the quadripolar lead group (n= 31). The LV leads were targeted to the basal LV segment in a vein concordant to the LV segment with the latest mechanical contraction chosen on the basis of preoperative radial strain (RS) echocardiography.Results: At the 6-month follow-up (FU), the reduction in LV end-systolic volume and LV reverse remodelling responder rate, defined as LV end-systolic volume reduction >15%, was 77% in the active fixation group and 83% in the quadripolar group, which was not significantly different. At the 12-month FU, the LV ejection fraction (LVEF) did not differ between the groups. There were no significant differences between the two groups in changes in New York Heart Association (NYHA) functional class or Minnesota Living with Heart Failure Questionnaire score. The occurrence of phrenic nerve stimulation (PNS) was 19% in the active fixation group versus 10% in the quadripolar group (p=.30), and all cases were resolved by reprogramming the device. All patients were alive at the 12-month FU. There was no device infection.Conclusions: There were no significant differences between the active fixation group of patients and the quadripolar group of patients concerning improvement in echocardiographic parameters or clinical symptoms.ClinicalTrials.gov number, NCT04632472.

The Roles of Fractionated Potentials in Non-Macroreentrant Atrial Tachycardias Following Atrial Fibrillation Ablation: Recognition Beyond Three-Dimensional Mapping.

Introduction: Non-macroreentrant atrial tachycardia (nAT) following atrial fibrillation (AF) ablation is being increasingly reported. Many issues remain to be elucidated. We aimed to characterize the fractionated potentials (FPs) in nAT and introduce a new method of cross-mapping for clarifying their roles. Methods and Results: Forty-four nATs in 37 patients were enrolled and classified into focal AT (FAT, 12), microreentrant AT (MAT, 14), and small-loop-reentrant AT (SAT, 18) groups, according to activation pattern. FP was found on all targets except in nine FATs. The ratio of FP duration to AT cycle length (TCL) was different among groups (28 ± 7% in FAT, 53 ± 11% in MAT, and 42 ± 14% in SAT, p < 0.05), and ablation duration were longer in SATs (313 ± 298 vs. 111 ± 125 s, p < 0.05). The ratio of mappable cycle length to TCL was lower in the FAT group (63 ± 22% vs. 90 ± 9% and 89 ± 8%, p < 0.05). When cross-mapping was employed, trans-potential time differences in both longitudinal and transverse direction were longer around the culprit FP for MAT (p < 0.01). After Receiver Operating Characteristic curve analysis, it is best to adopt the sum of time difference ratios in both directions ≥60% as a cut-off value for discrimination of the FPs responsible for MAT with a sensitivity of 92% and specificity of 87%. Conclusions: FP could be found on target in most nATs following a previous AF ablation. The ratio of FP duration to TCL may help for differentiation. A simple method of cross-mapping could be employed to clarify the roles of FPs.

Responsiveness of various reservoir species to oral rabies vaccination correlates with differences in vaccine uptake of mucosa associated lymphoid tissues.

Oral rabies vaccination (ORV) is highly effective in foxes and raccoon dogs, whereas for unknown reasons the efficacy of ORV in other reservoir species is less pronounced. To investigate possible variations in species-specific cell tropism and local replication of vaccine virus, different reservoir species including foxes, raccoon dogs, raccoons, mongooses, dogs and skunks were orally immunised with a highly attenuated, high-titred GFP-expressing rabies virus (RABV). Immunofluorescence and RT-qPCR screenings revealed clear differences among species suggesting host specific limitations to ORV. While for responsive species the palatine tonsils (tonsilla palatina) were identified as a main site of virus replication, less virus dissemination was observed in the tonsils of rather refractory species. While our comparison of vaccine virus tropism emphasizes the important role that the tonsilla palatina plays in eliciting an immune response to ORV, our data also indicate that other lymphoid tissues may have a more important role than originally anticipated. Overall, these data support a model in which the susceptibility to oral live RABV vaccine infection of lymphatic tissue is a major determinant in vaccination efficacy. The present results may help to direct future research for improving vaccine uptake and efficacy of oral rabies vaccines under field conditions.

Long-Term Immunogenicity and Efficacy of the Oral Rabies Virus Vaccine Strain SPBN GASGAS in Foxes.

: To evaluate the long-term immunogenicity of the live-attenuated, oral rabies vaccine SPBN GASGAS in a full good clinical practice (GCP) compliant study, forty-six (46) healthy, seronegative red foxes (Vulpesvulpes) were allocated to two treatment groups: group 1 (n = 31) received a vaccine bait containing 1.7 ml of the vaccine of minimum potency (106.6 FFU/mL) and group 2 (n = 15) received a placebo-bait. In total, 29 animals of group 1 and 14 animals of group 2 were challenged at 12 months post-vaccination with a fox rabies virus isolate (103.0 MICLD50/mL). While 90% of the animals offered a vaccine bait resisted the challenge, only one animal (7%) of the controls survived. All animals that had seroconverted following vaccination survived the challenge infection at 12 months post-vaccination. Rabies specific antibodies could be detected as early as 14 days post-vaccination. Based on the kinetics of the antibody response to SPBN GASGAS as measured in ELISA and RFFIT, the animals maintained stable antibody titres during the 12-month pre-challenge observation period at a high level. The results indicate that successful vaccination using the oral route with this new rabies virus vaccine strain confers long-term duration of immunity beyond one year, meeting the same requirements as for licensure as laid down by the European Pharmacopoeia.

Accuracy and usability of single-lead ECG from smartphones - A clinical study.

BACKGROUND: Several wireless ECG devices are commercially available for possible screening, monitoring and diagnosis of rhythms. The field is rapidly expanding, and some devices have demonstrated acceptable qualities. The objective was to evaluate the accuracy, usability and diagnostic capabilities of smartphone ECG in both patients and healthy controls. METHODS: We used a commercially available smartphone ECG device, connected wirelessly to a tablet, to record a 30-s lead I ECG in 144 subjects-20 of whom repeated the test after vigorous exercise. The subjects included 94 patients under standard calculated 12-lead ECG surveillance; transcripts were obtained shortly after the smartphone ECG was acquired. RESULTS: No significant differences were found in the QRS, frequency and QT intervals between the two modalities. Smartphone ECG recordings separated pathologic rhythms (atrial fibrillation (AF)/flutter, atrioventricular block, regular supraventricular rhythm, and pacing) from sinus rhythms with a sensitivity of 0.75 and a specificity of 0.97. The specific diagnosis of AF appeared in 11 patients and was detected with a sensitivity of 1 and a specificity of 0.94. There was a marginal decrease in the interpretability of the smartphone ECG after exercise. Inter- and intraobserver variability was low. CONCLUSIONS: Smartphone ECG accurately measures most baseline intervals and has acceptable sensitivity and specificity for pathological rhythms, especially for AF. Vigorous activity has a minor influence on the readability of the PR interval. Elderly patients may face challenges in recording a smartphone ECG correctly without assistance. According to our findings, the smartphone ECG would be applicable as a screening device for pathological rhythms.

Efficacy of the oral rabies virus vaccine strain SPBN GASGAS in foxes and raccoon dogs.

To test the immunogenicity and efficacy of a new oral rabies virus vaccine strain SPBN GASGAS in wildlife target species, one group of foxes and two groups of raccoon dogs were offered a bait containing 1.7 ml of the vaccine (106.6 FFU/ml; 106.8 FFU/dose) and subsequently challenged approximately 180 days later with a fox rabies virus isolate. One group of raccoon dogs (n=30) received the same challenge dose (100.7 MICLD50/ml) as the red foxes (n=29). The other group with raccoon dogs (n=28) together with 8 animals that received the vaccine dose by direct instillation into the oral cavity (DIOC) were infected with a 40-fold higher dose of the challenge virus (102.3 MICLD50/ml). All but one of the 29 vaccinated foxes survived the challenge infection; meanwhile all 12 control foxes succumbed to rabies. Twenty-eight of 30 vaccinated raccoon dogs challenged with the same dose survived the infection, however only six of 12 control animals succumbed. When the higher challenge dose was administered, all 12 control animals died from rabies and all 36 vaccinated animals (28 baited plus 8 DIOC) survived. Blood samples were collected at different time points post vaccination and examined by both RFFIT and ELISA. The kinetics of the measured immune response was similar for both species, although in RFFIT slightly higher values were observed in foxes than in raccoon dogs. However, the immune response as measured in ELISA was identical for both species. The oral rabies virus vaccine SPBN GASGAS meets the efficacy requirements for live rabies virus vaccines as laid down by the European Pharmacopoeia.

Entrapment and retrieval of a diagnostic electrophysiological catheter in the Chiari network.

The Chiari networks are reticulated fibers of embryological remnant venous valves in the right atrium. In patients with this congenital variation, manipulation of diagnostic catheters can be difficult, and there is a substantial risk of entrapment during electrophysiological studies. We report a case of successful retraction of a diagnostic catheter entangled in the Chiari network with the use of a lead extraction tool during a scheduled atrial fibrillation ablation. Rescheduled cryoablation was performed without complication and provided a good outcome.

Troponin T release comparing manually or magnetically guided radiofrequency ablation for AVNRT- a MAGMA AVNRT substudy.

OBJECTIVES: Catheter ablation is regarded as first-line therapy for symptomatic atrioventricular nodal reentry tachycardia (AVNRT). Ablation induces intended myocardial damage and the extent of myocardial damage may differ between ablation methods. The objective of this MAGMA AVNRT(NCT00875914) substudy was to compare high-sensitive cardiac troponin T (hs-cTnT) levels as a surrogate marker for myocardial damage after manually guided (MAN) AVNRT ablation versus AVNRT ablation using remote magnetic navigation (RMN). DESIGN: In total, 70 patients (mean age 44 ± 14 years, 26% male) undergoing catheter ablation for AVNRT in the MagMa-AVNRT-Trial were randomized to remote magnetic navigation (n = 34, 49%) or manually guided catheter ablation (n = 36, 51%). hs-cTnT was measured the day after the procedure. RESULTS: The median follow-up time was 6.2 ± 1.1 years. Acute success was 100% in both groups. hs-cTnT release was significantly lower in the remote magnetic navigation group (52 ng/L versus 95 ng/L, p < .01), even though the ablation time was longer and number of applications was higher with remote magnetic navigation (4.2 min vs 2.8 min, p = .017; 4.9 vs 3.3 applications, p = .01). hs-cTnT released per minute ablation time was also lower with remote magnetic navigation (12 ng/L versus 34 ng/L, p < .01). Both groups exhibited similar clinical long-term follow up regarding recurrence and complications. CONCLUSION: Remote magnetic navigation controlled catheter ablation of AVNRT has similar clinical outcome, but leads to less hs-cTnT release than manually guided catheter ablation. This might correspond to less unintended myocardial damage with RMN, which might be advantageous in complex ablation procedures.

In Vivo Safety Studies With SPBN GASGAS in the Frame of Oral Vaccination of Foxes and Raccoon Dogs Against Rabies.

In order to obtain Marketing Authorization for an oral rabies vaccine in the European Union, not only safety studies in the target species, red fox and raccoon dog, are required. Since baits are distributed unsupervised in the environment, specific safety studies in selected non-target species are compulsory. Furthermore, oral rabies vaccines are based on live, replication-competent viruses and thus distinct safety studies in the target species for such type of vaccines are also mandatory. Here, the results of these safety studies in target and selected non-target species for a 3rd generation oral rabies virus vaccine construct, SPBN GASGAS (Rabitec), are presented. The studies included the following species; red fox, raccoon dog, domestic dog, domestic cat, domestic pig, wild rodents. The following safety topics were investigated; overdose, repeated dose, dissemination, shedding, horizontal and vertical transmission. It was shown that SPBN GASGAS did not cause disease or any other adverse reaction in vaccinated animals and naïve contact animals. The vaccine did not disseminate within the host beyond the site of entry. No horizontal transmission was observed in wild rodents. In the target species, there was evidence that in a few cases horizontal transmission of vaccine virus could have occurred under these experimental conditions; most likely immediately after vaccine administration. The vaccine construct SPBN GASGAS meets therefore the latest revised minimal safety requirements as laid down in the European Pharmacopoeia.

Increased plasma trimethylamine-N-oxide is associated with incident atrial fibrillation.

BACKGROUND: Plasma trimethylamine-N-oxide (TMAO) is associated with cardiovascular disease; however specific relationships with cardiac arrhythmias are unknown. We evaluated the association between plasma TMAO and incident atrial fibrillation (AF). METHODS: Risk associations were explored among 3797 patients with suspected stable angina in the Western Norway Coronary Angiography Cohort (WECAC) and verified in 3143 elderly participants in the community-based Hordaland Health Study (HUSK). Information on endpoints was obtained from nationwide registries. RESULTS: Median follow-up was 7.3 and 10.8 years in the WECAC and HUSK cohorts, respectively, and 412 (10.9%) and 484 (15.4%) subjects were registered with incident AF. The age and gender adjusted HRs were 1.16, 95% CI 1.05-1.28 and 1.10, 95% CI 1.004-1.19 per 1 SD increase in log-transformed plasma TMAO. Adjusting for hypertension, BMI, smoking, diabetes, or intake of total choline, a TMAO precursor, did not materially influence the risk associations. Among patients in WECAC, further extensive adjustment for other AF risk factors yielded similar results. Adding TMAO to traditional AF risk factors (age, gender, hypertension, BMI, smoking and diabetes) yielded a continuous net reclassification improvement of 0.108, 95% CI 0.015-0.202 and 0.139, 95% CI 0.042-0.235. CONCLUSIONS: Plasma TMAO was associated with and improved reclassification of incident AF in two independent Norwegian cohorts with long-term follow-up. The relationship was independent of traditional AF risk factors, as well as of dietary choline intake. Our findings motivate further studies to explore endogenous metabolic factors influencing the relationship between TMAO and cardiovascular disease.