Hypertension and atrial fibrillation: the clinical impact of hypertension on perioperative outcomes of atrial fibrillation ablation and its optimal control for the prevention of recurrence.

Hypertension (HTN) is one of the major risk factors for developing atrial fibrillation (AF), and it has been estimated that approximately 70% of hypertensive patients are at risk of developing AF. On the other hand, 60-80% of AF patients have HTN. These two diseases share many risk factors such as diabetes mellitus, obesity, alcohol consumption, and sleep apnea syndrome during their onset and disease progression. The mutual presence of these diseases has the potential to create a negative spiral, exacerbating each other's impact and ultimately leading to cardiovascular events such as heart failure and cerebrovascular disorders, thereby increasing mortality rates. With regard to the treatment of HTN, the variety of antihypertensive drugs and treatment options have significantly increased. Alongside the widespread adoption of antihypertensive therapy, a certain level of efficacy has been recognized in suppressing the incidence of new-onset AF. Catheter ablation is an established and effective treatment for AF. However, a notable recurrence rate persists. In recent years, management of these multiple risk factors has been recognized to be essential for suppressing AF recurrence, and recent guidelines for AF underscore the significance of proactively managing these risks before treatment. Notably, effective HTN management assumes paramount importance given its impact on the morbidity of AF patients. This review summarizes the correlation between HTN control before and after ablation and the risk of AF recurrence. The focus is on elucidating the pathophysiological background and its impact on clinical outcomes.

Leveraging 3D Atrial Geometry for the Evaluation of Atrial Fibrillation: A Comprehensive Review.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia associated with significant morbidity and mortality. Managing risk of stroke and AF burden are pillars of AF management. Atrial geometry has long been recognized as a useful measure in achieving these goals. However, traditional diagnostic approaches often overlook the complex spatial dynamics of the atria. This review explores the emerging role of three-dimensional (3D) atrial geometry in the evaluation and management of AF. Advancements in imaging technologies and computational modeling have enabled detailed reconstructions of atrial anatomy, providing insights into the pathophysiology of AF that were previously unattainable. We examine current methodologies for interpreting 3D atrial data, including qualitative, basic quantitative, global quantitative, and statistical shape modeling approaches. We discuss their integration into clinical practice, highlighting potential benefits such as personalized treatment strategies, improved outcome prediction, and informed treatment approaches. Additionally, we discuss the challenges and limitations associated with current approaches, including technical constraints and variable interpretations, and propose future directions for research and clinical applications. This comprehensive review underscores the transformative potential of leveraging 3D atrial geometry in the evaluation and management of AF, advocating for its broader adoption in clinical practice.

NR4A3 prevents diabetes induced atrial cardiomyopathy by maintaining mitochondrial energy metabolism and reducing oxidative stress.

BACKGROUND: Atrial cardiomyopathy (ACM) is responsible for atrial fibrillation (AF) and thromboembolic events. Diabetes mellitus (DM) is an important risk factor for ACM. However, the potential mechanism between ACM and DM remains elusive. METHODS: Atrial tissue samples were obtained from patients diagnosed with AF or sinus rhythm (SR) to assess alterations in NR4A3 expression, and then two distinct animal models were generated by subjecting Nr4a3-/- mice and WT mice to a high-fat diet (HFD) and Streptozotocin (STZ), while db/db mice were administered AAV9-Nr4a3 or AAV9-ctrl. Subsequently, in vivo and in vitro experiments were conducted to assess the impact of NR4A3 on diabetes-induced atrial remodeling through electrophysiological, biological, and histological analyses. RNA sequencing (RNA-seq) and metabolomics analysis were employed to unravel the downstream mechanisms. FINDINGS: The expression of NR4A3 was significantly decreased in atrial tissues of both AF patients and diabetic mice compared to their respective control groups. NR4A3 deficiency exacerbated atrial hypertrophy and atrial fibrosis, and increased susceptibility to pacing-induced AF. Conversely, overexpression of NR4A3 alleviated atrial structural remodeling and reduced AF induction rate. Mechanistically, we confirmed that NR4A3 improves mitochondrial energy metabolism and reduces oxidative stress injury by preserving the transcriptional expression of Sdha, thereby exerting a protective influence on atrial remodeling induced by diabetes. INTERPRETATION: Our data confirm that NR4A3 plays a protective role in atrial remodeling caused by diabetes, so it may be a new target for treating ACM. FUNDING: This study was supported by the major research program of National Natural Science Foundation of China (NSFC) No: 82370316 (to Q-S. W.), No. 81974041 (to Y-P. W.), and No. 82270447 (to Y-P. W.) and Fundation of Shanghai Hospital Development Center (No. SHDC2022CRD044 to Q-S. W.).

Predictors of paroxysmal atrial fibrillation in patients with a cryptogenic stroke: Selecting patients for long-term rhythm monitoring.

BACKGROUND: After a cryptogenic stroke, patients often will require prolonged cardiac monitoring; however, the subset of patients who would benefit from long-term rhythm monitoring is not clearly defined. OBJECTIVE: The purpose of this study was to create a risk score by identifying significant predictors of atrial fibrillation (AF) using age, sex, comorbidities, baseline 12-lead electrocardiogram, short-term rhythm monitoring, and echocardiographic data and to compare it to previously published risk scores. METHODS: Patients admitted to Montefiore Medical Center between May 2017 and June 2022 with a primary diagnosis of cryptogenic stroke or transient ischemic attack who underwent long-term rhythm monitoring with an implantable cardiac monitor were retrospectively analyzed. RESULTS: Variables positively associated with a diagnosis of clinically significant AF include age (P <.001), race (P = .022), diabetes status (P = .026), chronic obstructive pulmonary disease status (P = .012), presence of atrial runs (P = .003), number of atrial runs per 24 hours (P <.001), total number of atrial run beats per 24 hours (P <.001), number of beats in the longest atrial run (P <.001), left atrial enlargement (P = .007), and at least mild mitral regurgitation (P = .009). We created a risk stratification score for our population, termed the ACL score. The ACL score demonstrated superiority to the CHA2DS2-VASc score and comparability to the C2HEST score for predicting device-detected AF. CONCLUSION: The ACL score enables clinicians to better predict which patients are more likely to be diagnosed with device-detected AF after a cryptogenic stroke.

Case report of a double-wave re-entry atrial flutter in a patient with atrial cardiomyopathy.

Background: Double-wave macrore-entry is a rare mechanism of atrial tachycardia with limited documentation in the literature. We present a three-dimensional documentation of a double-wave 'typical' atrial flutter in a patient with extensive atrial cardiomyopathy. Case summary: A 78-year-old female with a history of atrial cardiomyopathy and dual-chamber pacemaker for sinus node disease presented with palpitations and incessant atrial flutter. Electrophysiological study revealed a regular tachycardia with a cycle length (TCL) of 230 ms, with proximal to distal coronary sinus (CS) activation. Three-dimensional mapping identified two independent wavefronts circulating the cavotricuspid isthmus (CTI), each with a TCL of 460 ms. Cavotricuspid isthmus ablation resulted in conversion into a distinct tachycardia with left atrial roof origin. Linear ablation in this location slowed the TCL to 435 ms with concentric CS activation and another CTI dependent atrial flutter was mapped, this time with only one wavefront of activation. Further ablation with a second, more lateral, line in the CTI led to tachycardia interruption. Given the extensive atrial scarring and high arrhythmic recurrence risk, atrioventricular node ablation was performed. Discussion: Double-wave re-entrant tachycardias were primarily observed in experimental models, precipitating acceleration of ventricular and supraventricular tachycardias via extrastimulation. In our case, there is documentation of a spontaneous double-wave of activation around the CTI, representing the first documented double-wave 'typical' atrial flutter. Unlike other cases in the literature, the two wavefronts were equidistant, which resulted in a regular tachycardia with TCL that was half of the single-wave cycle length. Three-dimensional propagation mapping was essential to visualize the two distinct wavefronts.

Ischemic stroke and the emerging role of left atrial function.

INTRODUCTION: Ischemic stroke is a leading cause of morbidity and mortality worldwide. Emerging evidence suggests that left atrial (LA) dysfunction could play a role in the pathophysiology of ischemic stroke, as a possible contributor and as a predictive biomarker. AREAS COVERED: This narrative review details the intricate relationship between LA function, atrial fibrillation (AF), and ischemic stroke. We discuss imaging techniques used to assess LA function, the mechanisms by which impaired LA function may contribute to stroke, and its potential as a prognostic marker of stroke. EXPERT OPINION: There is a lack of evidence-based treatments of LA dysfunction in both primary and secondary stroke prevention. This is partly due to the lack of a practical clinical definition and unanswered questions concerning the clinical implications of LA dysfunction in patients without AF. Until such questions are resolved, addressing well-known cardiovascular risk factors, like hypertension and obesity, should be prioritized for preventing AF and ischemic stroke. These risk factors are closely tied to atrial remodeling, emphasizing the importance of targeting primary modifiable factors for preventing future morbidity and mortality.

Targeting the Substrate for Atrial Fibrillation: JACC Review Topic of the Week.

The identification of the pulmonary veins as a trigger source for atrial fibrillation (AF) has established pulmonary vein isolation (PVI) as a key target for AF ablation. However, PVI alone does not prevent recurrent AF in many patients, and numerous additional ablation strategies have failed to improve on PVI outcomes. This therapeutic limitation may be due, in part, to a failure to identify and intervene specifically on the pro-fibrillatory substrate within the atria and pulmonary veins. In this review paper, we highlight several emerging approaches with clinical potential that target atrial cardiomyopathy-the underlying anatomic, electrical, and/or autonomic disease affecting the atrium-in various stages of practice and investigation. In particular, we consider the evolving roles of risk factor modification, targeting of epicardial adipose tissue, tissue fibrosis, oxidative stress, and the inflammasome, along with aggressive early anti-AF therapy in AF management. Attention to combatting substrate development promises to improve outcomes in AF.

Atrial Cardiomyopathy Predicts the Functional Outcome and Mortality in Stroke Patients.

AIM: Atrial cardiomyopathy (ACM) is characterized by atrial dysfunction. This study aims to assess the prognostic significance of ACM in patients with noncardioembolic stroke (NCS). METHODS: Patients with NCS within seven days of onset were prospectively enrolled between January 2019 and December 2020. ACM was defined as either an N-terminal pro-brain natriuretic peptide (NT-pro BNP) ＞250 pg/ml or a P-terminal force in precordial lead V1 (PTFV1) ≥ 5000µV·ms. A poor functional outcome was determined as a score of 3-6 on the modified Rankin Scale (mRS) within a 2-year follow-up period. Logistic regression and Cox regression analyses were employed to examine the relationship between ACM and the long-term prognosis of patients with NCS. RESULTS: A total of 1,346 patients were enrolled, of whom 299 (22.2%) patients were diagnosed with ACM. A total of 207(15.4%) patients experienced a poor functional outcome, and 58 (4.3%) patients died. A multivariate logistic regression analysis indicated that ACM was significantly associated with a poor functional outcome in NCS patients [adjusted odds ratio (aOR): 2.01; 95% confidence interval (CI): 1.42-2.87; p＜0.001]. Additionally, a multivariate Cox regression analysis showed that an NT-pro BNP ＞250 pg/ml was significantly associated with an increased risk of all-cause mortality [adjusted hazard ratio (aHR), 2.51; 95% CI: 1.42-4.43; p=0.001]. CONCLUSIONS: ACM may serve as a novel predictor of a poor long-term functional outcome in patients with NCS. Elevated NT-pro BNP levels (＞250 pg/ml) were found to be associated with a higher risk of all-cause mortality. These findings warrant further validation in multicenter studies.

Long-term outcomes after catheter ablation for idiopathic atypical atrial flutter.

BACKGROUND: Idiopathic atypical (non-cavotricuspid isthmus-dependent) atrial flutter (IAAFL) may be seen in patients without structural heart disease and without previous cardiac surgery or ablation. OBJECTIVE: This study sought to determine the patient characteristics, electrophysiologic and electroanatomic properties, and clinical outcomes after ablation in patients with IAAFL. METHODS: We retrospectively compared IAAFL patients with cavotricuspid isthmus-dependent AFL (C-AFL) patients undergoing catheter ablation. The primary outcome was a composite of death from cardiovascular causes, ischemic stroke, and hospitalization for worsening of heart failure. RESULTS: Of 180 patients who underwent catheter ablation for AFL, 89 were included in this study (22 IAAFL and 67 C-AFL). Electrophysiologic study showed significantly longer intra-atrial conduction time and lower atrial voltage during sinus rhythm in the IAAFL group compared with the C-AFL group. The atrial scar was observed in all 22 IAAFL patients, with the most common sites being the posterior or lateral wall of the right atrium in 10 (45.5%) and the anterior wall of the left atrium in 8 (36.4%). During 3.5 ± 2.8 years of follow-up, the composite primary end point occurred significantly more frequently in the IAAFL group (hazard ratio [HR], 3.45; 95% confidence interval [CI], 1.20-9.89; P = .015). In multivariable analysis, brain natriuretic peptide levels (HR, 1.01; 95% CI, 1.00-1.01, per 1 pg/mL; P = .01) and IAAFL (HR, 4.14; 95% CI, 1.21-14.07; P = .02) were independently associated with the primary outcome. CONCLUSION: IAAFL in patients had distinct electrophysiologic features suggestive of atrial cardiomyopathy. These patients are at risk for development of cardiovascular adverse events after ablation.

Left Atrial Glucose Metabolism Evaluation by 18F-FDG-PET in Persistent Atrial Fibrillation and in Sinus Rhythm.

The role of atrial metabolism alterations for initiation and atrial fibrillation (AF) persistence remains poorly understood. Therefore, we evaluated left atrial glucose metabolism by nicotinic acid derivative stimulated 18-fluorodeoxyglucose positron emission tomography in 36 patients with persistent AF undergoing catheter ablation before and 3 months after return to sinus rhythm and compared values against healthy controls. Under identical hemodynamics and metabolic conditions, and although left ventricular FDG uptake remained unchanged, patients in persistent AF presented significantly higher total left atrial and left atrial appendage uptake, which decreased significantly after return to sinus rhythm, despite improvement of passive and active atrial contractile function. These findings support a role of altered glucose metabolism and metabolic wasting underlying the pathophysiology of persistent AF.

Longer and better lives for patients with atrial fibrillation: the 9th AFNET/EHRA consensus conference.

AIMS: Recent trial data demonstrate beneficial effects of active rhythm management in patients with atrial fibrillation (AF) and support the concept that a low arrhythmia burden is associated with a low risk of AF-related complications. The aim of this document is to summarize the key outcomes of the 9th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). METHODS AND RESULTS: Eighty-three international experts met in Münster for 2 days in September 2023. Key findings are as follows: (i) Active rhythm management should be part of the default initial treatment for all suitable patients with AF. (ii) Patients with device-detected AF have a low burden of AF and a low risk of stroke. Anticoagulation prevents some strokes and also increases major but non-lethal bleeding. (iii) More research is needed to improve stroke risk prediction in patients with AF, especially in those with a low AF burden. Biomolecules, genetics, and imaging can support this. (iv) The presence of AF should trigger systematic workup and comprehensive treatment of concomitant cardiovascular conditions. (v) Machine learning algorithms have been used to improve detection or likely development of AF. Cooperation between clinicians and data scientists is needed to leverage the potential of data science applications for patients with AF. CONCLUSIONS: Patients with AF and a low arrhythmia burden have a lower risk of stroke and other cardiovascular events than those with a high arrhythmia burden. Combining active rhythm control, anticoagulation, rate control, and therapy of concomitant cardiovascular conditions can improve the lives of patients with AF.

Left atrial cardiomyopathy: Pathophysiological insights, assessment methods and clinical implications.

Atrial cardiomyopathy is defined as any complex of structural, architectural, contractile or electrophysiological changes affecting atria, with the potential to produce clinically relevant manifestations. Most of our knowledge about the mechanistic aspects of atrial cardiomyopathy is derived from studies investigating animal models of atrial fibrillation and atrial tissue samples obtained from individuals who have a history of atrial fibrillation. Several noninvasive tools have been reported to characterize atrial cardiomyopathy in patients, which may be relevant for predicting the risk of incident atrial fibrillation and its related outcomes, such as stroke. Here, we provide an overview of the pathophysiological mechanisms involved in atrial cardiomyopathy, and discuss the complex interplay of these mechanisms, including aging, left atrial pressure overload, metabolic disorders and genetic factors. We discuss clinical tools currently available to characterize atrial cardiomyopathy, including electrocardiograms, cardiac imaging and serum biomarkers. Finally, we discuss the clinical impact of atrial cardiomyopathy, and its potential role for predicting atrial fibrillation, stroke, heart failure and dementia. Overall, this review aims to highlight the critical need for a clinically relevant definition of atrial cardiomyopathy to improve treatment strategies.

Loss of Cardiac Splicing Regulator RBM20 Is Associated With Early-Onset Atrial Fibrillation.

We showed an association between atrial fibrillation and rare loss-of-function (LOF) variants in the cardiac splicing regulator RBM20 in 2 independent cohorts. In a rat model with loss of RBM20, we demonstrated altered splicing of sarcomere genes (NEXN, TTN, TPM1, MYOM1, and LDB3), and differential expression in key cardiac genes. We identified altered sarcomere and mitochondrial structure on electron microscopy imaging and found compromised mitochondrial function. Finally, we demonstrated that 3 novel LOF variants in RBM20, identified in patients with atrial fibrillation, lead to significantly reduced splicing activity. Our results implicate alternative splicing as a novel proarrhythmic mechanism in the atria.

Practical approach for atrial cardiomyopathy characterization in patients with atrial fibrillation.

Atrial fibrillation (AF) causes progressive structural and electrical changes in the atria that can be summarized within the general concept of atrial remodeling. In parallel, other clinical characteristics and comorbidities may also affect atrial tissue properties and make the atria susceptible to AF initiation and its long-term persistence. Overall, pathological atrial changes lead to atrial cardiomyopathy with important implications for rhythm control. Although there is general agreement on the role of the atrial substrate for successful rhythm control in AF, the current classification oversimplifies clinical management. The classification uses temporal criteria and does not establish a well-defined strategy to characterize the individual-specific degree of atrial cardiomyopathy. Better characterization of atrial cardiomyopathy may improve the decision-making process on the most appropriate therapeutic option. We review current scientific evidence and propose a practical characterization of the atrial substrate based on 3 evaluation steps starting with a clinical evaluation (step 1), then assess outpatient complementary data (step 2), and finally include information from advanced diagnostic tools (step 3). The information from each of the steps or a combination thereof can be used to classify AF patients in 4 stages of atrial cardiomyopathy, which we also use to estimate the success on effective rhythm control.

Detection of subclinical atrial fibrillation with cardiac implanted electronic devices: What decision making on anticoagulation after the NOAH and ARTESiA trials?

Atrial fibrillation (AF) may be asymptomatic and the extensive monitoring capabilities of cardiac implantable electronic devices (CIEDs) revealed asymptomatic atrial tachi-arrhythmias of short duration (minutes-hours) occurring in patients with no prior history of AF and without AF detection at a conventional surface ECG. Both the terms "AHRE" (Atrial High-Rate Episodes) and subclinical AF were used in a series of prior studies, that evidenced the association with an increased risk of stroke. Two randomized controlled studies were planned in order to assess the risk-benefit profile of anticoagulation in patients with AHRE/subclinical AF: the NOAH and ARTESiA trials. The results of these two trials (6548 patients enrolled, overall) show that the risk of stroke/systemic embolism associated with AHRE/subclinical AF is in the range of 1-1.2 % per patient-year, but with an important proportion of severe/fatal strokes occurring in non-anticoagulated patients. The apparent discordance between ARTESiA and NOAH results may be approached by considering the related study-level meta-analysis, which highlights a consistent reduction of ischemic stroke with oral anticoagulants vs. aspirin/placebo (relative risk [RR] 0.68, 95 % CI 0.50-0.92). Oral anticoagulation was found to increase major bleeding (RR 1.62, 95 % CI 1.05-2.5), but no difference was found in fatal bleeding (RR 0.79, 95 % CI 0.37-1.69). Additionally, no difference was found in cardiovascular death or all-cause mortality. Taking into account these results, clinical decision-making for patients with AHRE/subclinical AF at risk of stroke, according to CHA2DS2-VASc, can now be evidence-based, considering the benefits and related risks of oral anticoagulants, to be shared with appropriately informed patients.

Cardiac-specific overexpression of CREM-IbΔC-X via CRISPR/Cas9 in mice presents a new model of atrial cardiomyopathy with spontaneous atrial fibrillation.

Atrial cardiomyopathy (ACM) forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. However, generating stable animal models that accurately replicate the entire progression of atrial lesions, particularly the onset of AF, presents significant challenges. In the present study, we found that the isoform of CRE-binding protein modulator (CREM-IbΔC-X), which is involved in the regulation of cardiac development and atrial rhythm, was highly expressed in atrial biopsies from patients with AF. Building upon this finding, we employed CRISPR/Cas9 technology to create a mouse model with cardiac-specific overexpression of CREM-IbΔC-X (referred to as CS-CREM mice). This animal model effectively illustrated the development of ACM through electrophysiological and structural remodelings over time. Proteomics and Chip-qPCR analysis of atrial samples revealed significant upregulation of cell-matrix adhesion and extracellular matrix structural components, alongside significant downregulation of genes related to atrial functions in the CS-CREM mice. Furthermore, the corresponding responses to anti-arrhythmia drugs, i.e., amiodarone and propafenone, suggested that CS-CREM mice could serve as an ideal in vivo model for drug testing. Our study introduced a novel ACM model with spontaneous AF by cardiac-specifically overexpressing CREM-IbΔC-X in mice, providing valuable insights into the mechanisms and therapeutic targets of ACM.