Ulrich Schotten

Background: Oral anticoagulation (OAC) reduces stroke risk in patients with atrial fibrillation (AF), and screening can enable earlier AF detection and OAC initiation. However, the population-level trade-off between stroke prevention and OAC-related major bleeding for different types of AF and OAC therapy remains uncertain, and large randomized trials to resolve this are costly and time-consuming. Methods: A state-transition Markov-like model was developed to: 1) simulate the lifetime course of AF, stroke, major bleeding, and death in different virtual populations; 2) quantify benefits (stroke reduction) and harms (major bleeding) of systematic AF screening with screening-triggered OAC across CHA ₂ DS ₂ -VA scores; and 3) compare rhythm-guided, time-delimited (“pill-in-pocket”) OAC with continuous OAC. Results: The model synthesized information from multiple clinical sources and reproduced stroke and bleeding incidence across clinical scenarios. At CHA₂DS₂-VA=2, long-term continuous rhythm monitoring (LT-CRM) with OAC lowered stroke risk (HR, 0.92 [95%CI, 0.88-0.96]) but raised bleeding risk (HR, 1.17 [95%CI, 1.07-1.27]) versus no screening. Time-to-benefit was shorter than time-to-harm for CHA₂DS₂-VA≥4, but longer for CHA₂DS₂-VA=0. Pill-in-pocket OAC vs continuous OAC showed no difference in stroke/mortality (HR, 1.03, 95%CI [0.91-1.16]) but lower bleeding risk (HR, 0.81, 95%CI: 0.68-0.96]) in patients with elevated bleeding risk, but not at baseline. Sensitivity analyses revealed that the risk-benefit profiles of screening or pill-in-pocket OAC strategy further depend on OAC adherence and bleeding risks. Conclusions: Our model highlights a trade-off between stroke reduction and bleeding for systematic screening-initiated OAC, with net benefit for CHA₂DS₂-VA≥4. We provide the first virtual implementation of an ongoing rhythm-guided OAC trial, showing that pill-in-pocket OAC may lower bleeding risk compared to continuous OAC, highlighting the potential of virtual clinical trials to guide clinical trial design.

Aims: In the heart, endogenous nicotinic acid adenine dinucleotide phosphate (NAADP) triggers lysosomal calcium (Ca2+) release to augment sarcoplasmic reticulum (SR) Ca2+ sequestration, producing larger Ca2+ transients. However, the role of lysosomal Ca2+ signals in pacemaker activity, a distinct Ca2+-operated function of the sinoatrial node (SAN), or in the atrial myocardium has not been investigated. Methods and results: Pharmacological or genetic ablation of the NAADP pathway inhibits the spontaneous beating rate response to β-adrenergic stimulation in intact SAN. We found intracellular signalling microdomains between lysosomes and neighbouring SR or mitochondria in mouse, and goat tissue. The spatial relationship between lysosomes and other Ca2+-handling organelles are altered in goat atrial fibrillation. Furthermore, we demonstrate atrial myocytes produce 3′-5′-cyclic adenosine monophosphate (cAMP) in response to lysosomal signalling, adding a novel trigger for cyclic nucleotide signalling. Conclusion: Our findings support the hypothesis that lysosomal Ca2+ signalling contributes to regulation of cardiomyocyte cAMP levels and pacemaker activity.

Purpose: Atrial fibrillation (AF) is both influenced by and contributes to atrial structural remodelling, including atrial enlargement and fibrosis. In this work, we aimed to understand how differences in atrial anatomy affect AF inducibility and dynamics, both without and with fibrosis, through in silico models. Methods: Atrial wall anatomies from late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) were used to generate personalised models. Detailed intra- and inter-atrial structures (pectinate muscles, Bachmann’s bundle, fossa ovalis, coronary sinus, and fibre orientations) were mapped onto patient-specific atrial anatomies through a novel strategy using universal atrial coordinates and a highly detailed reference model. Patient-specific endomysial fibrosis was incorporated based on LGE-MRI. We quantified AF and macro-reentrant atrial tachycardia (MRAT) initiation rates in models with and without fibrosis, comparing reentry dynamics using renewal theory. Results: We generated personalised models of 10 patients, all but one with low-fibrotic content (Utah stages ≤ 2). Anatomical variability did not significantly affect AF initiation rates in both non-fibrotic (54.0 ± 13.7%, p = 0.43) and fibrotic models (53.5 ± 15.3%, p = 0.37). For AF + MRAT, initiation rates varied significantly among fibrotic models ( p = 0.04) but not among non-fibrotic ones ( p = 0.14). Reentry formation rates varied significantly across anatomies both with and without fibrosis ( p < 0.04). With fibrosis, reentry destruction rates also varied significantly ( p < 0.02). The number of simultaneous reentries varied significantly across patient anatomies ( p < 0.001 without fibrosis, p < 0.05 with fibrosis), with fibrosis altering reentry counts in 2 patients ( p < 0.02). Conclusion: Atrial anatomy influenced patient-specific variability in AF reentry dynamics, while fibrosis played a limited modifying role in this low-fibrotic cohort.

Background and Aims: Atrial cardiomyopathy (AtCM) is associated with atrial fibrillation (AF). While histological studies describe underlying mechanisms of AtCM, these insights remain disconnected from clinical AtCM. This study determines the histological basis of non-invasive AtCM markers and assess their prognostic value in patients undergoing cardiac surgery. Methods and results: Left and right (LA/RA) atrial tissue samples were obtained in patients undergoing cardiac surgery (n = 136) in the RACE V Tissue Bank study. Pre-operative rhythm history, digital ECG, transthoracic echocardiography (TTE) and biomarker levels were used to group patients in AtCM stages: AF: history of paroxysmal, persistent or permanent AF, Severe (LAVi>50 mL/m2 or LAEF250 pg/mL), Mild (no AF, LAVi≤34 mL/m2 AND P-terminal Force V1 > 5 mV*ms OR P wave duration > 120 ms), and no AtCM. Tissue was stained (WGA/CD31/Vimentin) to quantify fibrosis, fibroblast density, myocyte diameter and vascularization. Post-operative rhythm was monitored continuously (2.5 years) using implantable loop recorders. Patients with severe AtCM had extended endomysial fibrosis (LA: +0.82µm, pFDR,LA < 0.001; RA: +0.64µm, pFDR,RA = 0.010) and larger left atrial cardiomyocytes (LA: +0.92µm, pFDR,LA = 0.026). Moderate AtCM patients showed LA myocyte hypertrophy (LA: +1.35µm, pFDR,LA = 0.007). Mild AtCM patients had similar histological features to patients without AtCM. Moderate (β = 3.56, pFDR = 0.045) and severe (β = 3.74, pFDR = 0.034) AtCM patients had a higher AF burden late after cardiac surgery. Conclusion: Clinical AtCM markers reflect pro-fibrotic and pro-hypertrophic remodelling in the moderate to severe AtCM stages and are associated with a higher AF burden late after surgery.

Background: Early rhythm control reduces cardiovascular events in patients with atrial fibrillation (AF) and cardiovascular comorbidities. Whether this effect is consistent across severities of different AF-associated conditions is not known. Methods: In the EAST-AFNET 4 biomolecule study (n=1,586; median age 70 years; 45% women), 14 circulating biomarkers reflecting inflammation, fibrosis, ageing, cardiac strain, and myocardial damage were quantified. Log-transformed, winsorized biomarkers were analysed in quintiles to detect non-linear associations and as continuous parameters. Cox proportional hazards models evaluated associations with the primary outcome (cardiovascular death, stroke, or unplanned hospitalization for heart failure or acute coronary syndrome) and the safety outcome (death, stroke, or major bleeding) of the trial, including interaction terms for biomarkers and randomized treatment (early rhythm control [ERC] vs usual care). [UC]). Two independent cohorts, BBC-AF resembling UC and a TRUST snapshot resembling ERC were combined for external replication. All tests were exploratory. Results: ERC reduced the primary outcome consistently across biomarker concentrations. No signal for treatment interaction was observed for 13 of 14 biomarkers for the primary outcome. For BMP10, a nominal interaction was observed in categorical analyses, suggesting an attenuated treatment effect of ERC in patients in the lowest BMP10 quintile. No interaction was detected for continuous parameters. Similar patterns were observed in exploratory analyses of the replication cohort. Conclusions: Early rhythm control therapy is effective across patients with different severities of conditions associated with atrial fibrillation as quantified by biomolecule concentrations. A potentially attenuated effect of ERC with low BMP10 concentrations warrants further research.

Aims: Symptom severity in atrial fibrillation (AF) influences healthcare use, but conventional assessments lack temporal precision. We evaluated the feasibility of smartphone-based symptom severity assessment after AF catheter ablation and explored predictors and variability of symptom severity. Methods and results: In this analysis of the ISOLATION study, 140 patients used a photoplethysmography-supported smartphone application to record heart rhythm, symptoms, and symptom severity three times daily and when symptomatic for 7 days at 3, 6, and 12 months after ablation. Symptom severity was classified using the modified European Heart Rhythm Association scale. A total of 8575 recordings were analysed, of which 11% showed AF. Median adherence was 67%. Symptom severity was higher during AF, in women, and with higher heart rate. Nearly half of AF recordings were asymptomatic. Conclusion: Smartphone-based symptom severity assessment after AF ablation is feasible and reveals substantial individual variability beyond rhythm status alone.

Aims: Atrial fibrillation (AF) is conventionally classified as paroxysmal or persistent. AF burden might better reflect response to rhythm-control interventions. This study evaluated the association between estimated pre-procedural time spent in AF and recurrences after AF ablation, compared with conventional AF classification. Methods and results: In patients scheduled for AF ablation, clinical characteristics were collected before ablation, and 60-second single-lead ECGs were recorded three times daily (with additional symptom-triggered recordings) for four weeks. Pre-procedural time spent in AF was estimated as the number of days with detected AF divided by total monitoring days. The primary endpoint was AF recurrence between 3 and 12 months post-ablation. Of 302 patients (mean age 64 ± 9 years; 33% female), 201 (67%) had paroxysmal AF and 101 (33%) had persistent AF. After 12 months, recurrence rates were higher in persistent than in paroxysmal AF (37.6% vs. 24.4%, P & 0.01) and in patients with a higher (>32%) vs. lower (≤32%) percentage of time spent in AF (36.4% vs. 24.0%, P < 0.01). Notably, paroxysmal AF patients with a higher percentage of time in AF had recurrence rates comparable to those of patients with persistent AF. Pre-procedural percentage of time in AF independently predicted arrhythmia recurrence at 12-month follow-up (HR: 1.06; 95% CI: 1.0–1.1; P & 0.025). Conclusion: A higher pre-procedural percentage of time spent in AF derived from 60-second single-lead ECGs is independently associated with atrial arrhythmia recurrence after ablation. Assessing the percentage of pre-procedural time spent in AF might help identify paroxysmal AF patients with a high AF recurrence risk in future studies.