Explore the vast range of titles available.

For both the atria and ventricles, fibrosis is generally recognized as one of the key determinants of conduction disturbances. By definition, fibrosis refers to an increased amount of fibrous tissue. However, fibrosis is not a singular entity. Various forms can be distinguished, that differ in distribution: replacement fibrosis, endomysial and perimysial fibrosis, and perivascular, endocardial, and epicardial fibrosis. These different forms typically result from diverging pathophysiological mechanisms and can have different consequences for conduction. The impact of fibrosis on propagation depends on exactly how the patterns of electrical connections between myocytes are altered. We will therefore first consider the normal patterns of electrical connections and their regional diversity as determinants of propagation. Subsequently, we will summarize current knowledge on how different forms of fibrosis lead to a loss of electrical connectivity in order to explain their effects on propagation and mechanisms of arrhythmogenesis, including ectopy, reentry, and alternans. Finally, we will discuss a histological quantification of fibrosis. Because of the different forms of fibrosis and their diverging effects on electrical propagation, the total amount of fibrosis is a poor indicator for the effect on conduction. Ideally, an assessment of cardiac fibrosis should exclude fibrous tissue that does not affect conduction and differentiate between the various types that do; in this article, we highlight practical solutions for histological analysis that meet these requirements.

A trial fibrillation (AF), the most common human cardiac arrhythmia, is associated with abnormal intracellular Ca2+ handling. Diastolic Ca2+ release from the sarcoplasmic reticulum via \"leaky\" ryanodine receptors (RyR2s) is hypothesized to contribute to arrhythmogenesis in AF, but the molecular mechanisms are incompletely understood. Here, we have shown that mice with a genetic gain-of-function defect in Ryr2 (which we termed Ryr2R176Q/+ mice) did not exhibit spontaneous AF but that rapid atrial pacing unmasked an increased vulnerability to AF in these mice compared with wild-type mice. Rapid atrial pacing resulted in increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2, while both pharmacologic and genetic inhibition of CaMKII prevented AF inducibility in Ryr2R176Q/+ mice. This result suggests that AF requires both an arrhythmogenic substrate (e.g., RyR2 mutation) and enhanced CaMKII activity. Increased CaMKII phosphorylation of RyR2 was observed in atrial biopsies from mice with atrial enlargement and spontaneous AF, goats with lone AF, and patients with chronic AF. Genetic inhibition of CaMKII phosphorylation of RyR2 in Ryr2S2814A knockin mice reduced AF inducibility in a vagotonic AF model. Together, these findings suggest that increased RyR2-dependent Ca2+ leakage due to enhanced CaMKII activity is an important downstream effect of CaMKII in individuals susceptible to AF induction.

To bridge the current gap between the known mechanisms of atrial fibrillation (AF) and the clinical management of patients with this arrhythmia, Fabritz and colleagues propose a roadmap to develop a set of clinical markers that reflect the major causes of AF in patients. A new, mechanism-based classification of AF can provide the basis for personalized prevention and management. Despite remarkable advances in antiarrhythmic drugs, ablation procedures, and stroke-prevention strategies, atrial fibrillation (AF) remains an important cause of death and disability in middle-aged and elderly individuals. Unstructured management of patients with AF sharply contrasts with our detailed, although incomplete, knowledge of the mechanisms that cause AF and its complications. Altered calcium homeostasis, atrial fibrosis and ageing, ion-channel dysfunction, autonomic imbalance, fat-cell infiltration, and oxidative stress, in addition to a susceptible genetic background, contribute to the promotion, maintenance, and progression of AF. However, clinical management of patients with AF is currently guided by stroke risk parameters, AF pattern, and symptoms. In response to this apparent disconnect between the known pathophysiology of AF and clinical management, we propose a roadmap to develop a set of clinical markers that reflect the major causes of AF in patients. Thereby, the insights into the mechanisms causing AF will be transformed into a format that can underpin future personalized strategies to prevent and treat AF, ultimately informing better patient care.

Early detection of atrial fibrillation (AF) enables initiation of anticoagulation and early rhythm control therapy to reduce stroke, cardiovascular death, and heart failure. In a cross-sectional, observational study, we aimed to identify a combination of circulating biomolecules reflecting different biological processes to detect prevalent AF in patients with cardiovascular conditions presenting to hospital. Twelve biomarkers identified by reviewing literature and patents were quantified on a high-precision, high-throughput platform in 1485 consecutive patients with cardiovascular conditions (median age 69 years [Q1, Q3 60, 78]; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. Logistic regression with backward elimination and a neural network approach considering 7 key clinical characteristics and 12 biomarker concentrations were applied to a randomly sampled discovery cohort (n = 933) and validated in the remaining patients (n = 552). In addition to age, sex, and body mass index (BMI), BMP10, ANGPT2, and FGF23 identified patients with prevalent AF (AUC 0.743 [95% CI 0.712, 0.775]). These circulating biomolecules represent distinct pathways associated with atrial cardiomyopathy and AF. Neural networks identified the same variables as the regression-based approach. The validation using regression yielded an AUC of 0.719 (95% CI 0.677, 0.762), corroborated using deep neural networks (AUC 0.784 [95% CI 0.745, 0.822]). Age, sex, BMI and three circulating biomolecules (BMP10, ANGPT2, FGF23) are associated with prevalent AF in unselected patients presenting to hospital. Findings should be externally validated. Results suggest that age and different disease processes approximated by these three biomolecules contribute to AF in patients. Our findings have the potential to improve screening programs for AF after external validation.

Background Atrial fibrillation has an estimated prevalence of 1.5–2%, making it the most common cardiac arrhythmia. The processes that cause and sustain the disease are still not completely understood. An association between atrial fibrillation and systemic, as well as local, inflammatory processes has been reported. However, the exact mechanisms underlying this association have not been established. While it is understood that inflammatory macrophages can influence cardiac electrophysiology, a direct, causative relationship to atrial fibrillation has not been described. This study investigated the pro-arrhythmic effects of activated M1 macrophages on human induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes, to propose a mechanistic link between inflammation and atrial fibrillation. Methods Two hiPSC lines from healthy individuals were differentiated to atrial cardiomyocytes and M1 macrophages and integrated in an isogenic, pacing-free, atrial fibrillation-like coculture model. Electrophysiology characteristics of cocultures were analysed for beat rate irregularity, electrogram amplitude and conduction velocity using multi electrode arrays. Cocultures were additionally treated using glucocorticoids to suppress M1 inflammation. Bulk RNA sequencing was performed on coculture-isolated atrial cardiomyocytes and compared to meta-analyses of atrial fibrillation patient transcriptomes. Results Multi electrode array recordings revealed M1 to cause irregular beating and reduced electrogram amplitude. Conduction analysis further showed significantly lowered conduction homogeneity in M1 cocultures. Transcriptome sequencing revealed reduced expression of key cardiac genes such as SCN5A , KCNA5 , ATP1A1, and GJA5 in the atrial cardiomyocytes . Meta-analysis of atrial fibrillation patient transcriptomes showed high correlation to the in vitro model. Treatment of the coculture with glucocorticoids showed reversal of phenotypes, including reduced beat irregularity, improved conduction, and reversed RNA expression profiles. Conclusions This study establishes a causal relationship between M1 activation and the development of subsequent atrial arrhythmia, documented as irregularity in spontaneous electrical activation in atrial cardiomyocytes cocultured with activated macrophages. Further, beat rate irregularity could be alleviated using glucocorticoids. Overall, these results point at macrophage-mediated inflammation as a potential AF induction mechanism and offer new targets for therapeutic development. The findings strongly support the relevance of the proposed hiPSC-derived coculture model and present it as a first of its kind disease model.

Heart disease, as well as systemic metabolic alterations, can leave a ‘fingerprint’ of structural and functional changes in the atrial myocardium, leading to the onset of atrial cardiomyopathy. As demonstrated in various animal models, some of these changes, such as fibrosis, cardiomyocyte hypertrophy and fatty infiltration, can increase vulnerability to atrial fibrillation (AF), the most relevant manifestation of atrial cardiomyopathy in clinical practice. Atrial cardiomyopathy accompanying AF is associated with thromboembolic events, such as stroke. The interaction between AF and stroke appears to be far more complicated than initially believed. AF and stroke share many risk factors whose underlying pathological processes can reinforce the development and progression of both cardiovascular conditions. In this review, we summarize the main mechanisms by which atrial cardiomyopathy, preceding AF, supports thrombogenic events within the atrial cavity and myocardial interstitial space. Moreover, we report the pleiotropic effects of activated coagulation factors on atrial remodeling, which may aggravate atrial cardiomyopathy. Finally, we address the complex association between AF and stroke, which can be explained by a multidirectional causal relation between atrial cardiomyopathy and hypercoagulability.

Successful translation of research focussing on atrial arrhythmogenic mechanisms has potential to provide a mechanism-tailored classification and to support personalised treatment approaches in patients with AF. The clinical uptake and clinical implementation of new diagnostic techniques and treatment strategies require translational research approaches on various levels. Diagnostic translation involves the development of clinical diagnostic tools. Additionally, multidisciplinary teams are required for collaborative translation to describe genetic mechanisms, molecular pathways, electrophysiological characteristics and concomitant risk factors. In this article, current approaches for AF substrate characterisation, analysis of genes potentially involved in AF and strategies for AF risk factor assessment are summarised. The authors discuss challenges and obstacles to clinical translation and implementation into clinical practice.

Background Early postoperative atrial fibrillation (early-POAF) is the most common complication after cardiac surgery. Although prior studies have demonstrated an association between early-POAF and late outcomes, it is questionable whether these long-term adverse events result from early-POAF or from comorbidities that underlie the development of early-POAF. Therefore, the aim of this study was to investigate the association of early-POAF with late mortality and stroke after adjustment for age and cardiovascular comorbidities. Methods A systematic search was conducted to identify studies reporting on late mortality after cardiac surgery in patients with and without early-POAF. Articles presenting Kaplan–Meier were included for a pooled analysis of late mortality (primary outcome) and stroke (secondary outcome). Individual time-to-event data were reconstructed from the Kaplan–Meier curves and incorporated into a multivariable mixed-effects Cox model. Results In total, 33 studies were included in the analysis for late mortality (131 031 patients) and 10 studies in the analysis for late stroke (42 042 patients). Overall, 36 991 patients had early-POAF with a pooled incidence of 31.5% (95% CI: 27.7 to 35.6%). Unadjusted analysis showed that early-POAF was significantly associated with late mortality (Hazard Ratio [HR] = 1.62, 95%CI: 1.58–1.67, P  < 0.001) and late stroke (HR = 1.72, 95%CI: 1.61–1.85, P  < 0.001). Early-POAF was significantly associated with late mortality (adjusted HR = 1.19, 95% CI: 1.07–1.33, P  = 0.002), but not with late stroke (adjusted HR = 1.14, 95% CI: 0.96–1.35, P  = 0.122) after adjustment for age, comorbidities, surgery type, and the random effects term. Conclusion Early-POAF after cardiac surgery is significantly associated with late mortality, but not with late stroke, after adjustments for age, sex, cardiovascular comorbidities, and type of surgery.

Aims: The acetylcholine-activated inward rectifier potassium current (I KACh ) has been proposed as an atrial-selective target for the treatment of atrial fibrillation (AF). Using a novel selective I KACh inhibitor XAF-1407, the study investigates the effect of I KACh inhibition in goats with pacing-induced, short-term AF. Methods: Ten goats (57 ± 5 kg) were instrumented with pericardial electrodes. Electrophysiological parameters were assessed at baseline and during intravenous infusion of XAF-1407 (0.3, 3.0 mg/kg) in conscious animals before and after 2 days of electrically induced AF. Following a further 2 weeks of sustained AF, cardioversion was attempted with either XAF-1407 (0.3 followed by 3 mg/kg) or with vernakalant (3.7 followed by 4.5 mg/kg), an antiarrhythmic drug that inhibits the fast sodium current and several potassium currents. During a final open chest experiment, 249 unipolar electrograms were recorded on each atrium to construct activation patterns and AF cardioversion was attempted with XAF-1407. Results: XAF-1407 prolonged atrial effective refractory period by 36 ms (45%) and 71 ms (87%) (0.3 and 3.0 mg/kg, respectively; pacing cycle length 400 ms, 2 days of AF-induced remodeling) and showed higher cardioversion efficacy than vernakalant (8/9 vs. 5/9). XAF-1407 caused a minor decrease in the number of waves per AF cycle in the last seconds prior to cardioversion. Administration of XAF-1407 was associated with a modest increase in QTc (<10%). No ventricular proarrhythmic events were observed. Conclusion: XAF-1407 showed an antiarrhythmic effect in a goat model of AF. The study indicates that I KACh represents an interesting therapeutic target for treatment of AF. To assess the efficacy of XAF-1407 in later time points of AF-induced remodeling, follow-up studies with longer period of AF maintenance would be necessary.

BackgroundBiochemical markers of inflammation, coagulation and myocardial stress have been associated with both prevalent and incident atrial fibrillation (AF), but little is known about the relationship between biomarker expression and AF burden.AimsOur aim was to investigate the association between cardiovascular biomarkers and AF burden and AF episode duration ≥24 hours.Methods and resultsIn this multicentre observational cohort study, we included 404 patients with paroxysmal AF from the Reappraisal of Atrial Fibrillation: Interaction between Hypercoagulability, Electrical Remodelling and Vascular Destabilisation in the Progression of AF study and evaluated a total of 92 potential cardiovascular blood biomarkers. All patients completed 1 year of follow-up with continuous rhythm monitoring using an implanted loop recorder or a dual-chamber pacemaker. The relationship between biomarker expression and AF was investigated using multiple regression including nine preselected covariates: age, sex, prior heart failure, hypertension, renal insufficiency, prior stroke, coronary artery disease, body mass index and treatment with antiarrhythmic drugs. Elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were associated with higher AF burden (incidence rate ratio 1.75, 95% CI 1.75 to 2.06) and AF episode duration ≥24 hours (OR 1.78, 95% CI 1.39 to 2.27). Increased levels of matrix metalloproteinase 2, neurogenic locus notch homologue protein 3 and tumour necrosis factor receptor 2 were additionally associated with AF episode durations ≥24 hours.ConclusionsHigher circulating levels of NT-proBNP are associated with increased AF burden and AF episode duration ≥24 hours in patients with paroxysmal AF.Trial registration numberNCT02726698.