Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models

The mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to establish an atrial filtration (AF) model in our laboratory, we profiled several commonly used murine AF models. We initially evaluated a pharmacological model of acute carbachol (CCh) treatment plus atrial burst pacing in C57BL/6 mice. In an effort to observe micro-reentrant circuits indicative of authentic AF, we employed optical mapping imaging in isolated mouse hearts. While CCh reduced atrial refractoriness and increased atrial tachyarrhythmia vulnerability, the left atrial (LA) excitation patterns were rather regular without reentrant circuits or wavelets. Therefore, the atrial tachyarrhythmia resembled high frequency atrial flutter, not typical AF per se. We next examined both a chronic angiotensin II (Ang II) infusion model and the surgical model of transverse aortic constriction (TAC), which have both been reported to induce atrial and ventricular structural changes that serve as a substrates for micro-reentrant AF. Although we observed some extent of atrial remodeling such as fibrosis or enlarged LA diameter, burst pacing-induced atrial tachyarrhythmia vulnerability did not differ from control mice in either model. This again suggested that an AF-like pathophysiology is difficult to demonstrate in the mouse. To continue searching for a valid murine AF model, we studied mice with a cardiac-specific deficiency (KO) in liver kinase B1 (Cardiac-LKB1), which has been reported to exhibit spontaneous AF. Indeed, the electrocardiograms (ECG) of conscious Cardiac-LKB1 KO mice exhibited no P waves and had irregular RR intervals, which are characteristics of AF. Histological evaluation of Cardiac-LKB1 KO mice revealed dilated and fibrotic atria, again consistent with AF. However, atrial electrograms and optical mapping revealed that electrical activity was limited to the sino-atrial node area with no electrical conduction into the atrial myocardium beyond. Thus, Cardiac-LKB1 KO mice have severe atrial myopathy or atrial standstill, but not AF. In summary, the atrial tachyarrhythmias we observed in the four murine models were distinct from typical human AF, which often exhibits micro- or macro-reentrant atrial circuits. Our results suggest that the four murine AF models we examined may not reflect human AF well, and raise a cautionary note for use of those murine models to study AF.

Atrial fibrillation driver identification through regional mutual information networks: a modeling perspective

Purpose Effective identification of electrical drivers within remodeled tissue is a key for improving ablation treatment for atrial fibrillation. We have developed a mutual information, graph-based approach to identify and propose fault tolerance metric of local efficiency as a distinguishing feature of rotational activation and remodeled atrial tissue. Methods Voltage data were extracted from atrial tissue simulations (2D Karma, 3D physiological, and the Multiscale Cardiac Simulation Framework (MSCSF)) using multi-spline open and parallel regional mapping catheter geometries. Graphs were generated based on varied mutual information thresholds between electrode pairs and the local efficiency for each graph was calculated. Results High-resolution mapping catheter geometries can distinguish between rotational and irregular activation patterns using the derivative of local efficiency as a function of increasing mutual information threshold. The derivative is decreased for rotational activation patterns comparing to irregular activations in both a simplified 2D model (0.0017 ± 1 × 10−4 vs. 0.0032 ± 1 × 10−4, p < 0.01) and a more realistic 3D model (0.00092 ± 5 × 10−5 vs. 0.0014 ± 4 × 10−5, p < 0.01). Average local efficiency derivative can also distinguish between degrees of remodeling. Simulations using the MSCSF model, with 10 vs. 90% remodeling, display distinct derivatives in the grid design parallel spline catheter configuration (0.0015 ± 5 × 10−5 vs. 0.0019 ± 6 × 10−5, p < 0.01) and the flower shaped open spline configuration (0.0011 ± 5 × 10−5 vs. 0.0016 ± 4 × 10−5, p < 0.01). Conclusion A decreased derivative of local efficiency characterizes rotational activation and varies with atrial remodeling. This suggests a distinct communication pattern in cardiac rotational activation detectable via high-resolution regional mapping and could enable identification of electrical drivers for targeted ablation.

Athlete’s Heart in Elite Biathlon, Nordic Cross—Country and Ski-Mountaineering Athletes: Cardiac Adaptions Determined Using Echocardiographic Data

Twelve world elite Biathlon (Bia), ten Nordic Cross Country (NCC) and ten ski-mountaineering (Ski-Mo) athletes were evaluated for pronounced echocardiographic physiological cardiac remodeling as a primary aim of our descriptive preliminary report. In this context, sports-related cardiac remodeling was analyzed by performing two-dimensional echocardiography including speckle tracking analysis as left ventricular global longitudinal strain (LV-GLS). A multicenter retrospective analysis of echocardiographic data was performed in 32 elite world winter sports athletes, which were obtained between 2020 and 2021 during the annual medical examination. The matched data of the elite world winter sports athletes (14 women, 18 male athletes, age: 18–35 years) were compared for different echocardiographic parameters. Significant differences could be revealed for left ventricular systolic function (LV-EF, p = 0.0001), left ventricular mass index (LV Mass index, p = 0.0078), left atrial remodeling by left atrial volume index (LAVI, p = 0.0052), and LV-GLS (p = 0.0003) between the three professional winter sports disciplines. This report provides new evidence that resting measures of cardiac structure and function in elite winter sport professionals can identify sport specific remodeling of the left heart, against the background of training schedule and training frequency.

Region-specific distribution of transversal-axial tubule system organization underlies heterogeneity of calcium dynamics in the right atrium

The atrial myocardium demonstrates the highly heterogeneous organization of the transversal-axial tubule system (TATS), while its anatomical distribution and region-specific impact on Ca2+ dynamics remain unknown. We developed a novel method for high-resolution confocal imaging of TATS in intact live mouse atrial myocardium and applied a Matlab-based computational algorithm for the automated analysis of TATS integrity. We observed a 2-fold higher (P<0.01) TATS density in the right atrial appendage (RAA) than in the inter-caval region (ICR, the anatomical region between the superior vena cava and atrioventricular junction and between the crista terminalis and inter-atrial septum). While RAA predominantly consisted of well-tubulated myocytes, ICR showed partially tubulated/untubulated cells. Similar TATS distribution was also observed in healthy human atrial myocardium sections. In both mouse atrial preparations and isolated mouse atrial myocytes, we observed a strong anatomical correlation between TATS distribution and Ca2+ transient synchronization and rise-up time. This region-specific difference in Ca2+ transient morphology disappeared after formamide-induced detubulation. ICR myocytes showed a prolonged action potential duration at 80% of repolarization as well as a significantly lower expression of RyR2 and Cav1.2 proteins, but similar levels of NCX1 and Cav1.3 compared to RAA tissue. Our findings provide a detailed characterization of the region-specific distribution of TATS in mouse and human atrial myocardium highlighting the structural foundation for anatomical heterogeneity of Ca2+ dynamics and contractility in the atria. These results could indicate different roles of TATS in Ca2+ signaling at distinct anatomical regions of the atria and provide mechanistic insight into pathological atrial remodeling.

Sex-Related Differences in Atrial Remodeling in Patients With Atrial Fibrillation: Relationship to Ablation Outcomes

Background: Population studies have demonstrated a range of sex differences including a higher prevalence of atrial fibrillation (AF) in men and a higher risk of AF recurrence in women. However, the underlying reasons for this higher recurrence are unknown. This study evaluated whether sex-based electrophysiological substrate differences exist to account for worse AF ablation outcomes in women. Methods: High-density electroanatomic mapping of the left atrium was performed in 116 consecutive patients with AF. Regional analysis was performed across 6 left atrium segments. High-density maps were created using a multipolar catheter (Biosense Webster) during distal coronary sinus pacing at 600 and 300 ms. Mean voltage and conduction velocity was determined. Complex fractionated signals and double potentials were manually annotated. Results: Overall, 42 (36%) were female, mean age was 61±8 years and AF was persistent in 52%. Global mean voltage was significantly lower in females compared with males at 600 ms (1.46±0.17 versus 1.84±0.15 mV, P <0.001) and 300 ms (1.27±0.18 versus 1.57±0.18 mV, P =0.013) pacing. These differences were seen uniformly across the left atrium. Females demonstrated significant conduction velocity slowing (34.9±6.1 versus 44.1±6.9 cm/s, P =0.002) and greater proportion of complex fractionated signals (9.9±1.7% versus 6.0±1.7%, P =0.014). After a median follow-up of 22 months (Q1–Q3: 15–29), females had significantly lower single-procedure (22 [54%] versus 54 [75%], P =0.029) and multiprocedure (24 [59%] versus 60 [83%], P =0.005) arrhythmia-free survival. Female sex and persistent AF were independent predictors of single and multiprocedure arrhythmia recurrence. Conclusions: Female patients demonstrated more advanced atrial remodeling on high-density electroanatomic mapping and greater post-AF ablation arrhythmia recurrence compared with males. These changes may contribute to sex-based differences in the clinical course of females with AF and in part explain the higher risk of recurrence.

Utility of Speckle-Tracking Echocardiography For Predicting Atrial Fibrillation Following Ischemic Stroke: A Systematic Review And Meta-Analysis

Purpose: Undiagnosed atrial fibrillation (AF) is one of the main sources of cryptogenic stroke. And strain indices measured by speckle-tracking echocardiography are associated with atrial remodeling supposed to be the substrate of AF. Therefore, there is a strong need for evaluating the utility of speckle-tracking echocardiography to predict the likelihood of AF in patients with cryptogenic stroke.Methods: PubMed, Embase and Cochrane Database were searched for studies. The random-effects model was used to calculate the pooled results, and summary receiver operating characteristic curve (SROC) analysis was performed to show the overall predictive value.Results: There were 1483 patients with cryptogenic stroke from 8 studies. Meta-analysis showed that strain indices including global longitudinal strain (GLS) (mean difference [SMD]: -0.22, 95% confidence interval [95% CI]: -0.40 to -0.04) , left atrial reservoir strain (εR), (SMD: -0.87, 95% CI: -1.26 to -0.48, conduit strain (εCD) (SMD: -0.56, 95% CI: -0.81 to -0.30), contractile strain (εCT) (SMD: -1.00, 95% CI: -1.39 to -0.61), and left atrial reservoir strain rate (SRe) (SMD: -0.54, 95% CI: -0.80 to -0.28) measured at the period of cryptogenic stroke was significantly decreased in patients with AF occurrence compared to without. SROC analysis suggested an acceptable predictive efficiency of εR for AF occurrence (AUC = 0.799).Conclusion: For patients after cryptogenic stroke, GLS, εR, εCD, εCT and SRe were significantly decreased in AF occurrence compared with non-occurrence. But there was no value in left atrial reservoir strain rate (SRs) and contractile strain rate (SRa) for predicting AF.

Left Atrial Remodeling and Cerebrovascular Disease Assessed by Magnetic Resonance Imaging in Continuously Monitored Patients

<b><i>Background:</i></b> Atrial remodeling is associated with future atrial fibrillation (AF) and stroke. AF has been associated with cognitive impairment and cerebral white matter lesions. We wished to investigate the possible direct association between atrial remodeling and cerebrovascular disease in patients with and without AF documented by implantable loop recorder (ILR). <b><i>Methods:</i></b> Cardiac and cerebral magnetic resonance imaging were acquired in a cross-sectional study, including participants ≥70 years of age with stroke risk factors without known AF. Cerebrovascular disease was visually rated using the Fazekas scale and number of lacunar strokes. Left atrial (LA) and ventricular volumes and function were analyzed. Associations between atrial remodeling and cerebrovascular disease were assessed with logistic regression models. The analyses were stratified according to sinus rhythm or any AF during 3 months of continuous ILR monitoring to account for subclinical AF. <b><i>Results:</i></b> Of 200 participants investigated, 87% had a Fazekas score ≥1 and 45% had ≥1 lacunar infarct. Within 3 months of ILR monitoring, AF was detected in 28 (14%) participants. For participants with sinus rhythm (<i>n</i> = 172), lower LA passive emptying fraction was associated with Fazekas score after multivariable adjustment (OR [95% CI]: 0.51 [0.27; 0.86] <i>p</i> = 0.02), and increased LA maximum (OR [95% CI]: 1.38 [1.07; 1.82] <i>p</i> = 0.01) and minimum volumes (OR [95% CI]: 1.48 [1.03; 2.17] <i>p</i> = 0.04) were associated with lacunar infarcts. There were no significant associations in patients with AF. <b><i>Conclusion:</i></b> In AF-free patients, as documented by ILR monitoring, we found an independent association between LA passive emptying fraction and Fazekas score and between atrial volumes and lacunar infarcts.