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.

Atrial Cardiomyopathy: a Role in the Pathogenesis of Atrial Fibrillation and Influence on the Results of Its Treatment

The work is dedicated to the issue of atrial cardiomyopathies (ACs). They have a significant effect on the heart function, provoke rhythm disturbances and increase the risk of thromboembolic complications. The aim. To analyze the latest publications on the topic. The material for the analysis were the papers published by the leading arrhythmological clinics. Discussion. This paper describes the origin of the term “atrial cardiomyopathy”, highlights the conditional classification of changes in the atrial myocardium according to the EHRAS classification. The causes of this nosological form may be some types of gene mutations, as well as hypertension, congestive circulatory failure, diabetes mellitus, myocarditis, etc. ACs play an important role in the occurrence of atrial fibrillation (AF) and also affect its natural course and treatment outcomes. Electroanatomical mapping and magnetic resonance data show significant fibrotic changes in the atria in individuals with this form of arrhythmia. The DECAAF study (Delayed enhancement MRI and atrial fibrillation catheter ablation) showed that fibrotic changes in the atrial myocardium are directly related to the frequency of recurrent arrhythmias after catheter ablation. The DECAAFII study confirmed the effectiveness of the influence on the fibrous substrate in the catheter treatment of AF at stages 1 and 2 of fibrosis. The results of catheter treatment depend on the severity of fibrosis, which shows the importance of taking this factor into account when determining the indications for ablation. Conclusions. Thus, AC is an important component of the pathogenesis of AF. Improvement of techniques for influencing the fibrous substrate will improve the results of catheter treatment of AF.

Inferior Extensions of the Atrioventricular Node

The pathways for excitation of the atrioventricular node enter either superiorly, as the so-called ‘fast’ pathway, or inferiorly as the ‘slow’ pathway. However, knowledge of the specific anatomical details of these pathways is limited. Most of the experimental studies that established the existence of these pathways were conducted in mammalian hearts, which have subtle differences to human hearts. In this review, the authors summarise their recent experiences investigating human cardiac development, correlating these results with the arrangement of the connections between the atrial myocardium and the compact atrioventricular node as revealed by serial sectioning of adult human hearts. They discuss the contributions made from the atrioventricular canal myocardium, as opposed to the primary ring. Both these rings are incorporated into the atrial vestibules, albeit with the primary ring contributing only to the tricuspid vestibule. The atrial septal cardiomyocytes are relatively late contributors to the nodal inputs. Finally, they relate our findings of human cardiac development to the postnatal arrangement.

Ischemic Heart Disease Selectively Modifies the Right Atrial Appendage Transcriptome

Background: Although many pathological changes have been associated with ischemic heart disease (IHD), molecular-level alterations specific to the ischemic myocardium and their potential to reflect disease severity or therapeutic outcome remain unclear. Currently, diagnosis occurs relatively late and evaluating disease severity is largely based on clinical symptoms, various imaging modalities, or the determination of risk factors. This study aims to identify IHD-associated signature RNAs from the atrial myocardium and evaluate their ability to reflect disease severity or cardiac surgery outcomes.Methods and Results: We collected right atrial appendage (RAA) biopsies from 40 patients with invasive coronary angiography (ICA)-positive IHD undergoing coronary artery bypass surgery and from 8 patients ICA-negative for IHD (non-IHD) undergoing valvular surgery. Following RNA sequencing, RAA transcriptomes were analyzed against 429 donors from the GTEx project without cardiac disease. The IHD transcriptome was characterized by repressed RNA expression in pathways for cell–cell contacts and mitochondrial dysfunction. Increased expressions of the CSRNP3, FUT10, SHD, NAV2-AS4, and hsa-mir-181 genes resulted in significance with the complexity of coronary artery obstructions or correlated with a functional cardiac benefit from bypass surgery.Conclusions: Our results provide an atrial myocardium-focused insight into IHD signature RNAs. The specific gene expression changes characterized here, pave the way for future disease mechanism-based identification of biomarkers for early detection and treatment of IHD.

The Changes of Gene Expression and Protein Level of Stretch-Activated Chloride Channel in Atrial Myocardium of Dogs with Atrial Fibrillation

Introduction: ICl,stretch have been reported to be involved in the development of atrial fibrillation, so we observed the changes of transcription and translation levels of ICl,stretch in isolated atrial myocardium of heart failure canine models. Material and methods: In the control group (N = 10), five dogs were untreated and the other five received sham operation, while dogs in the heart failure group (N = 10) were implanted with cardiac pacemakers and underwent right ventricular pacing to induce heart failure. Cardiac structure and function were evaluated. The gene expression and protein level of ICl,stretch in the left atrial appendage were detected. Results: The left atrial diameter, right atrial dimension, left ventricular diastolic dimension, and right ventricular diastolic dimension were significantly larger in the heart failure group (P < 0.05). In contrast, the ejection fraction and the left ventricular shorten fraction were higher in the control group (P < 0.05). Both the mRNA and protein expression levels of ICl,stretch in atrial myocardium of the heart failure group were significantly higher compared with the control group. Conclusion: ICl,stretch might play an important role in the vulnerability to atrial fibrillation in dilated atria with heart failure and could be a potential therapeutic target for atrial fibrillation.

Substrate Modification in Catheter Treatment of Atrial Fibrillation

According to modern concepts, atrial fibrillation (AF) occurs when there are triggers affecting the prepared substrate (atrial myocardium) in the presence of modulating factors that contribute to the occurrence of arrhythmia. Catheter treatment of AF has been most successfully developed in the field of affecting triggers (since late 1990s, the most successful was a technique of isolation of pulmonary veins which are the main source of trigger impulses in AF). Over the past two decades, various techniques have also been proposed for influencing the fibrous substrate. The aim. To analyze the most advanced techniques for influencing the fibrous substrate during catheter treatment of AF. Materials and methods. We analyzed the experience of leading electrophysiological centers in this field. Discussion. Modern studies contain various electrophysiological criteria of fibrous myocardium. However, the signal amplitude less than 0.5 mV is considered borderline between healthy and damaged tissues by most authors. The task of the catheter action on the myocardium is to separate the fibrously altered tissue and intact tissue. This can be achieved by isolating the area of fibrosis or by transforming it into a scar tissue incapable of arrhythmogenesis. It should be noted that both methods are associated with the same frequency of the absence of AF paroxysms, which can be regarded as confirmation of the advisability of influencing the substrate. The most important is that exposure of the substrate can significantly reduce the recurrence rate of AF compared to that when the ablation procedure is limited to isolation of the pulmonary veins. Conclusions. Modern methods of influencing the areas of fibrosis in the atria can significantly improve the results of catheter treatment of AF.

Cyclic Variation of Spectral Parameters for the Differentiation of Atrial Myocardium Before and Immediately Following Radiofrequency Ablation

Radiofrequency ablation (RFA) is a common treatment of atrial fibrillation. However, current treatment is associated with a greater than 20% recurrence rate, in part due to inadequate monitoring of tissue viability during ablation. Spectral parameters, in particular cyclic variation of integrated backscatter (CVIB), have shown promise as early indicators of myocardial recovery from ischemia. Our aim was to demonstrate the use of spectral parameters to differentiate atrial myocardium before and after radiofrequency ablation. An AcuNav 10 F catheter was used to collect radiofrequency signals from the posterior wall of the left atrium of patients before and immediately after RFA for AF. The normalized power spectrum was obtained and three spectral parameters (integrated backscatter [IB], slope, and intercept) were extracted across two continuous heart cycles. Parameters were gated for ventricular end-diastole and compared before and after ablation. Additionally, the cyclic variation of each of these three parameters was generated as an average of the variation across the two recorded heart cycles. Data from 14 patients before and after ablation demonstrated a significant difference in the magnitude of the cyclic variation of integrated backscatter (9.0 vs. 6.0 dB, p < .001) and cyclic variation of the intercept (14.0 vs. 11.5 dB, p = .04). No significant difference was noted in the magnitude of the cyclic variation of the slope. Among spectral parameters gated for end-diastole, significant differences were noted in the slope (−4.39 vs. −3.73 dB/MHz, p = .002) and intercept (16.8 vs. 11.9 dB, p = .002). No significant difference was noted in the integrated backscatter. Spectral parameters are able to differentiate atrial myocardium before and immediately following ablation and may be useful in monitoring atrial ablations.

ANGPTL4 Attenuates Ang II-Induced Atrial Fibrillation and Fibrosis in Mice via PPAR Pathway

Atrial fibrillation (AF) is the more significant portion of arrhythmia in clinical practice, with inflammation and fibrosis as its central pathological mechanisms. This study aimed to investigate angiopoietin-like 4 (ANGPTL4) effects on angiotensin II- (Ang II-) induced AF and its related pathophysiological mechanisms. C57BL/6J mice were randomized and divided into three groups: the control group, the Ang II group, and the ANGPTL4 group (Ang II with ANGPTL4 treatment). Mice were infused with Ang II (2000 ng/kg/min) and were administrated with recombinant human ANGPTL4 (rhANGPTL4, 20 μg/kg/day) for 3 weeks. The fibrosis was evaluated with Masson’s trichrome staining in the atrial myocardium. mRNA levels of IL-1β, IL-6, collagen I, and collagen III were measured using real-time qRT-PCR. Protein levels of PPARα, PPARγ, CPT-1, and SIRT3 were measured using Western blotting. Compared to the control group, the mice infused with Ang II showed electrocardiogram characteristics of AF, and this effect was markedly attenuated in ANGPTL4-treated mice. ANGPTL4 also reversed the increase in cardiomyocyte apoptosis, inflammation, interstitial collagen fraction, and collagen gene expression in mice with Ang II. Mechanistically, ANGPTL4 inhibited the activation of several fatty acid metabolism-related proteins, including PPARα, PPARγ, and CPT-1, and the expression of SIRT3 protein in atrial tissues. In conclusion, ANGPTL4 attenuates Ang II-induced AF and atrial fibrosis by modulation in the SIRT3, PPARα, and PPARγ signaling pathways.

The Electrophysiology of Atrial Fibrillation: From Basic Mechanisms to Catheter Ablation

The electrophysiology of atrial fibrillation (AF) has always been a deep mystery in understanding this complex arrhythmia. The pathophysiological mechanisms of AF are complex and often remain unclear despite extensive research. Therefore, the implementation of basic science knowledge to clinical practice is challenging. After more than 20 years, pulmonary vein isolation (PVI) remains the cornerstone ablation strategy for maintaining the sinus rhythm (SR). However, there is no doubt that, in many cases, especially in persistent and long-standing persistent AF, PVI is not enough, and eventually, the restoration of SR occurs after additional intervention in the rest of the atrial myocardium. Substrate mapping is a modern challenge as it can reveal focal sources or rotational activities that may be responsible for maintaining AF. Whether these areas are actually the cause of the AF maintenance is unknown. If this really happens, then the targeted ablation may be the solution; otherwise, more rough techniques such as atrial compartmentalization may prove to be more effective. In this article, we attempt a broad review of the known pathophysiological mechanisms of AF, and we present the recent efforts of advanced technology initially to reveal the electrical impulse during AF and then to intervene effectively with ablation.