Pathology Of Atrial Fibrillation Research Articles

Atrial cardiomyocytes from a canine model of atrial fibrillation demonstrate reduced force development and altered expression of contractile proteins.

Atrial fibrillation (AF) is the most common cardiac rhythm disturbance and associates with worse outcomes in cardiac contractile-related diseases including cardiomyopathy. As most studies surrounding AF focus on the electrophysiology of the disease, there is little known about cardiomyocyte contractile function in AF. We used atrial tissue from an established atrial tachypacing canine model of AF. Whole protein lysates were collected from the atria to conduct mass spectrometry analysis showing dysregulation of numerous molecular pathways, including contractility. Skinned atrial cardiomyocytes were isolated from the tissue for force calcium and passive tension experiments. Force calcium experiments showed a significant reduction in the maximum force of contraction of AF cardiomyocytes. To explain this, myosin heavy chain (MHC) isoform expression was evaluated because isoform switching is known to alter force of contraction. Decreased percent beta expression was found, explaining the reduction of force due to MHC alpha's capacity for reduced force of contraction. AF cardiomyocytes showed increased calcium sensitivity of force development, which may translate to prolonged contraction with slower relaxation in vivo. A significant reduction in S100A1 was seen in the AF samples via mass spectrometry, which is associated with increased calcium sensitivity. Prolonged contraction along with reduced force of each contraction could support the development of atrial clots. Atrial cardiomyocytes from the AF hearts demonstrated a significant reduction in the passive tension. Evaluation of titin isoform expression, which is known to alter passive tension, showed increased titin degradation, supporting the capacity for atrial dilation in vivo. Discerning the role of contractility in the pathology of atrial fibrillation could provide novel avenues of AF treatment, especially in instances where it is associated with contractile diseases.

Fetal cardiomyocyte phenotype, ketone body metabolism, and mitochondrial dysfunction in the pathology of atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia diagnosed in clinical practice. Even though hypertension, congestive heart failure, pulmonary disease, and coronary artery disease are the potential risk factors for AF, the underlying molecular pathology is largely unknown. The reversion of the mature cardiomyocytes to fetal phenotype, impaired ketone body metabolism, mitochondrial dysfunction, and the cellular effect of reactive oxygen species (ROS) are the major underlying biochemical events associated with the molecular pathology of AF. On this background, the present manuscript sheds light into these biochemical events in regard to the metabolic derangements in cardiomyocyte leading to AF, especially with respect to structural, contractile, and electrophysiological properties. In addition, the article critically reviews the current understanding, potential demerits, and translational strategies in the management of AF.

Identification of atrial fibrillation-associated microRNAs in left and right atria of rheumatic mitral valve disease patients.

MicroRNA (miRNA) is associated with the development and pathology of atrial fibrillation (AF). In this study, we performed miRNA profiling of left and right atrium samples from individuals with AF-associated rheumatic mitral valve disease (RMVD) to identify miRNAs that are differentially expressed between RMVD patients with AF and RMVD with sinus rhythm (SR) as controls, as well as between left and right atrium samples from RMVD with AF patients. We performed hematoxylin and eosin staining as well as scanning and transmission electron microscopy to examine in detail any morphological and physiological changes in cardiomyocytes from RMVD patients with AF or SR. Raman spectroscopy was performed to identify molecular and structural information of left and right atrium samples from RMVD with AF and SR. We also performed miRNA array profiling to separately profile miRNA expression patterns of right and left atrium samples from three independent RMVD patients with AF and in a mixed pool of 10 RMVD patients with SR. Morphological and physiological analysis showed distinct shapes and structures of cardiomyocytes from the left and right atria of RMVD patients with AF or SR. The intensity of Raman spectroscopy of atrial tissues from RMVD patients with AF and with SR was different. miRNA profiling showed differential miRNA expression between RMVD patients with AF or SR, and between the left and right atria of RMVD patients with AF. Importantly, miRNAs showed consistent expression changes among all three patients, suggesting that these miRNAs have potential as markers for AF pathology. Our results revealed potential biomarker miRNAs for atrial fibrillation pathology in patients with RMVD. Meanwhile, our data suggested that miR-10b and miR-138-2, which were both significantly increased in the left atrium, are responsible for morphological and physiological phenotype differences between the left and right atria.

Increased Extracellular Nucleosome Levels and Microparticles in Atrial Fibrillation Patients Compared to the Age-Matched Normal Population

Introduction: Atrial fibrillation (AF) is currently the most common cardiac arrhythmia encountered in clinical practice and a major cause of morbidity and mortality among adults. It is estimated that atrial fibrillation affects approximately 2.7 million people in the United States. Extracellular plasma nucleosomes (PNs) are complexes of DNA and histones that are released during cell death. Histones have been shown to function as DAMPs when they are translocated from the nucleus to the extracellular space. It is hypothesized that these extracellular nucleosomes contribute to the observed hypercoagulable state and embolic complications in AF.Methods: The concentration of PNs in 48 plasma samples of atrial fibrillation patients and 38 aged-matched controls were measured using the Cell Death Detection ELISA PLUS assay (Roche Diagnostics, Mannheim, Germany) and functional microparticle levels were measured using an annexin binding method (Hyphen Biomedical, Paris, France).Results: When comparing the concentration of nucleosomes in plasma, the atrial fibrillation patients (306.1 ± 328.86 μg/mL) had much higher levels than the aged-matched controls (177.9 ± 146.7 μg/mL), (p = 0.0015). Functional microparticles were also markedly elevated in the AF patients (18.6 ± 4.1 nM) in comparison to the aged-matched controls (4.6 ± 3.1 nM), (p=0.001). A significant correlation was observed between the PN’s and microparticles, (p < 0.05).Conclusion: Both the microparticles and PNs were elevated in atrial fibrillation when compared to aged-matched controls, suggesting increased cell death resulting in the generation of these biomarkers. Extracellular nucleosomes function as DAMPs by binding to receptors and triggering the activation of multiple signal pathways which may contribute to the elevation of microparticles. Due to the involvement of inflammation and thrombosis in the pathology of atrial fibrillation, the simultaneously increased circulating nucleosome and microparticle levels in patients with AF implies their role in the pathogenesis of this syndrome. DisclosuresNo relevant conflicts of interest to declare.

Nitrated fatty acids suppress angiotensin II-mediated fibrotic remodelling and atrial fibrillation.

Atrial fibrosis, one of the most striking features in the pathology of atrial fibrillation (AF), is promoted by local and systemic inflammation. Electrophilic fatty acid nitroalkenes, endogenously generated by both metabolic and inflammatory reactions, are anti-inflammatory mediators that in synthetic form may be useful as drug candidates. Herein we investigate whether an exemplary nitro-fatty acid can limit atrial fibrosis and AF. Wild-type C57BL6/J mice were treated for 2 weeks with angiotensin II (AngII) and vehicle or nitro-oleic acid (10-nitro-octadec-9-enoic acid, OA-NO2, 6 mg/kg body weight) via subcutaneous osmotic minipumps. OA-NO2 significantly inhibited atrial fibrosis and depressed vulnerability for AF during right atrial electrophysiological stimulation to levels observed for AngII-naive animals. Left atrial epicardial mapping studies demonstrated preservation of conduction homogeneity by OA-NO2. The protection from fibrotic remodelling was mediated by suppression of Smad2-dependent myofibroblast transdifferentiation and inhibition of Nox2-dependent atrial superoxide formation. OA-NO2 potently inhibits atrial fibrosis and subsequent AF. Nitro-fatty acids and possibly other lipid electrophiles thus emerge as potential therapeutic agents for AF, either by increasing endogenous levels through dietary modulation or by administration as synthetic drugs.

The pathology of atrial fibrillation in dogs

Atrial fibrillation (AF) occurs in dogs in a number of settings, the most common of which is congestive heart failure. This paper reviews what is known about the pathology of AF in dogs, as well as its clinical relevance. We begin by discussing several experimental AF paradigms in dogs, the associated pathology, and its relevance to AF mechanisms. We then discuss clinical AF in dogs and its relationship to experimental pathology. Finally, we conclude by assessing the potential therapeutic relevance of understanding AF-related pathology in dogs, as well as its potential to have practical applications in the future.

Pathology of atrial fibrillation in man.

Pathology of atrial fibrillation in man.