Functional Genomic Study on Atrial Fibrillation Using cDNA Microarray and Two‐Dimensional Protein Electrophoresis Techniques and Identification of the Myosin Regulatory Light Chain Isoform Reprogramming in Atrial Fibrillation

Lai, Ling‐Ping; Lin, Jia Wei; Lin, Chun‐Jen; Yeh, Ho‐Ming; Tsay, Yeou Guang; Lee, Chwen-Fang; Lee, Hsiao-Hui; Chang, Zee-Fen; Hwang, Juey‐Jen; Su, Ming‐Jai; Tseng, Yung‐Zu; Huang, Shoei K. Stephen

doi:10.1046/j.1540-8167.2004.03423.x

Cited by 54 publications

(40 citation statements)

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“…Even though steroid eluding pacing catheters were used, the pig model demonstrated the problematic tendency to encapsulate the electrodes, leading to the inability to pace the atria and to induce sustained AF. While several studies (6,(17)(18)(19) of RAP-induced AF in pigs have been published, none of these reports have models of AF in pigs of Ͼ6 wk in duration. There is inconsistency concerning the effect of AF on LV EF and atrial fibrosis in these published studies (see Table 3).…”

Section: Discussionmentioning

confidence: 99%

Chronic atrial fibrillation causes left ventricular dysfunction in dogs but not goats: experience with dogs, goats, and pigs

Dosdall

Ranjan

Higuchi

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Structural remodeling in chronic atrial fibrillation (AF) occurs over weeks to months. To study the electrophysiological, structural, and functional changes that occur in chronic AF, the selection of the best animal model is critical. AF was induced by rapid atrial pacing (50-Hz stimulation every other second) in pigs (n ϭ 4), dogs (n ϭ 8), and goats (n ϭ 9). Animals underwent MRIs at baseline and 6 mo to evaluate left ventricular (LV) ejection fraction (EF). Dogs were given metoprolol (50 -100 mg po bid) and digoxin (0.0625-0.125 mg po bid) to limit the ventricular response rate to Ͻ180 beats/min and to mitigate the effects of heart failure. The pacing leads in pigs became entirely encapsulated and lost the ability to excite the heart, often before the onset of sustained AF. LV EF in dogs dropped from 54 Ϯ 11% at baseline to 33 Ϯ 7% at 6 mo (P Ͻ 0.05), whereas LV EF in goats did not drop significantly (69 Ϯ 8% at baseline vs. 60 Ϯ 9% at 6 mo, P ϭ not significant). After 6 mo of AF, fibrosis levels in dog atria and ventricles increased, whereas only atrial fibrosis levels increased in goats compared with control animals. In our experience, the pig model is not appropriate for chronic rapid atrial pacing-induced AF studies. Rate-controlled chronic AF in the dog model developed HF and LV fibrosis, whereas the goat model developed only atrial fibrosis without ventricular dysfunction and fibrosis. Both the dog and goat models are representative of segments of the patient population with chronic AF. animal models; chronic atrial fibrillation; fibrosis; heart failure; rapid atrial pacing ATRIAL FIBRILLATION (AF) is the most frequent chronic arrhythmia (22) and significantly increases the risk of stroke and mortality (7). AF currently affects ϳ3 million patients in the United States alone, and its prevalence is predicted to increase to Ͼ7.5 million by the year 2050 (20). Despite significant advances in treatment options, including rhythm and rate control techniques, AF is frequently recurrent and persistent.A significant limitation in the development of broadly effective treatments for AF is that the development of the substrate that leads to longstanding persistent AF is not well understood. It is well known that "AF begets AF," or, in other words, the longer AF persists, the more likely it is that a patient will experience more AF in the future (30). Numerous studies (1,8,24,29,33,34) have demonstrated that there are significant structural and electrophysiological substrate changes that accompany chronic AF.Recent studies (14,15,26,27) have shown that whereas electrical remodeling and sustained AF may be achieved in a matter of weeks, tissue levels and structural remodeling continue over months. Patients with longstanding persistent AF exhibit different activation patterns and have higher AF recurrence rates than patients with paroxysmal AF (11,25,31). Chronic large animal models of sustained AF provide the opportunity to study the development of the substrate that leads to AF persistence and recurrence. The purpose ...

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Section: Discussionmentioning

confidence: 99%

Chronic atrial fibrillation causes left ventricular dysfunction in dogs but not goats: experience with dogs, goats, and pigs

Dosdall

Ranjan

Higuchi

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…18, 19 Moreover, a recent microarray study using a pig model of AF showed that the gene changes are more pronounced in the LA than the RA, with considerable overlap in the gene response. 20 Another previous study compared differences in 517 proteins that were expressed differently in the LAA between the SR and AF patients were associated with high-level functions and utilities of the biological system were identified. Metabolism-and cardiovascular disease-related proteins play an important role in the LAA tissue of AF patients.…”

Section: Main Findingmentioning

confidence: 99%

Quantitative Proteomics of Changes in Energy Metabolism-Related Proteins in Atrial Tissue From Valvular Disease Patients With Permanent Atrial Fibrillation

Zhou

Liu

et al. 2014

Circ J

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“…5 To explore the hypothesis that pmAF leads to upregulation of ventricular transcripts other than those encoding for contractile proteins, we used a genome-wide approach to compare atrial mRNA expression of patients with pmAF to atrial mRNA expression of patients with sinus rhythm (SR) as well as to ventricular (LV) gene expression. Our findings indicate that pmAF leads to repression of atrial transcriptional activity and induces a ventricular-like genomic signature in atrial myocardium.…”

mentioning

confidence: 99%

Reprogramming of the Human Atrial Transcriptome in Permanent Atrial Fibrillation

Barth¹,

Merk²,

Arnoldi³

et al. 2005

Circulation Research

189

172

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Abstract-Atrial fibrillation is associated with increased expression of ventricular myosin isoforms in atrial myocardium, regarded as part of a dedifferentiation process. Whether reexpression of ventricular isoforms in atrial fibrillation is restricted to transcripts encoding for contractile proteins is unknown. Therefore, this study compares atrial mRNA expression in patients with permanent atrial fibrillation to atrial mRNA expression in patients with sinus rhythm and to ventricular gene expression using Affymetrix U133 arrays. In atrial myocardium, we identified 1434 genes deregulated in atrial fibrillation, the majority of which, including key elements of calcium-dependent signaling pathways, displayed downregulation. Functional classification based on Gene Ontology provided the specific gene sets of the interdependent processes of structural, contractile, and electrophysiological remodeling. In addition, we demonstrate for the first time a prominent upregulation of transcripts involved in metabolic activities, suggesting an adaptive response to increased metabolic demand in fibrillating atrial myocardium. Ventricular-predominant genes were 5 times more likely to be upregulated in atrial fibrillation (174 genes upregulated, 35 genes downregulated), whereas atrial-specific transcripts were predominantly downregulated (56 genes upregulated, 564 genes downregulated). Overall, in fibrillating atrial myocardium, functional classes of genes characteristic of ventricular myocardium were found to be upregulated (eg, metabolic processes), whereas functional classes predominantly expressed in atrial myocardium were downregulated (eg, signal transduction and cell communication). Therefore, dedifferentiation with adoption of a ventricular-like signature is a general feature of the fibrillating atrium. Key Words: atrial fibrillation Ⅲ gene expression Ⅲ atrial myocardium Ⅲ functional genomics A trial fibrillation (AF), the most common sustained arrhythmia, is associated with extensive structural, contractile, and electrophysiological remodeling, 1 stabilizing AF in the long run. Because current pharmacological treatment of AF is limited by ventricular proarrhythmia and inefficacy to prevent recurrences of AF, understanding the molecular events of these remodeling processes is essential for the development of new targeted therapeutic interventions. Even though knowledge of genes involved in remodeling processes exists on a gene-by-gene basis including transcripts of the extracellular matrix compartment, 2 ion channels, 1,3 and signal transduction molecules, 4 microarray analysis offers a broader and unbiased approach to identify pathophysiologically relevant pathways. Therefore, we performed a systematic functional analysis of gene expression in permanent atrial fibrillation (pmAF) based on information from the Gene Ontology (GO) database to relate expression changes of single transcripts to known remodeling processes.Moreover, atrial fibrillation has been shown to be associated with an atrial-to-ventricular switch by expr...

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Functional Genomic Study on Atrial Fibrillation Using cDNA Microarray and Two‐Dimensional Protein Electrophoresis Techniques and Identification of the Myosin Regulatory Light Chain Isoform Reprogramming in Atrial Fibrillation

Abstract: Both cDNA microarray and two-dimensional polyacrylamide protein electrophoresis studies revealed characteristic changes in AF tissue. We demonstrated the reprogramming of myosin regulatory light chain isoform composition, with a significant increase of its ventricular isoform (MLC-2V).

Cited by 54 publications

References 23 publications

Chronic atrial fibrillation causes left ventricular dysfunction in dogs but not goats: experience with dogs, goats, and pigs

Chronic atrial fibrillation causes left ventricular dysfunction in dogs but not goats: experience with dogs, goats, and pigs

Quantitative Proteomics of Changes in Energy Metabolism-Related Proteins in Atrial Tissue From Valvular Disease Patients With Permanent Atrial Fibrillation

Reprogramming of the Human Atrial Transcriptome in Permanent Atrial Fibrillation

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