Unknown,Transcriptomics,Genomics,Proteomics

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A microRNA blueprint for early atrial remodeling in a porcine model of paroxysmal atrial fibrilation

ABSTRACT: Spontaneous paroxysmal atrial fibrillation (PAF) is one of the very common heart rhythm disorders. The molecular mechanisms underlying PAF susceptibility and persistence are multiple and incompletely understood. To study the contribution of microRNAs (miRNAs) to the development and perpetuation of PAF, we used microarray/qPCR analyses to search for changes in miRNA expression in atrial myocardium upon pacing-induced PAF. The miRNA microarray analysis was performed at LC Sciences (Houston, TX, USA). Following screening-microarray, several miRNAs were selected for detailed real-time qPCR assay. Our results suggest that immediate-early miR remodeling of LAA underlies the development and persistence of PAF. A closed-chest model of PAF was established in postnatal pigs via a rapid atrial electrical stimulation with a controlled ventricular response rate. A pacing catheter (delivered into the right atrium via femoral vein access under fluoroscopic guidance) was connected with an external pulse generator for programmed pacing rates. The burst-pacing stimuli were repeated several times, and the induced PAF occurrence rates and durations were recorded. Burst pacing was not performed in sham-operated group. Animals were euthanized 24 hours after cessation of pacing. Given that the right atrium might have been damaged by catheter insertion, we studied miRNA expression changes associated with PAF in the left atrial appendage (LAA) from paced vs control pigs. Six piglet were randomized in two groups, the PAF group (3 replicates) and the sham-control group (3 replicates)

ORGANISM(S): Sus scrofa

SUBMITTER: Mario Torrado

PROVIDER: E-GEOD-65330 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Sustained atrial tachycardia leads to multiple molecular and cellular effects collectively defined as atrial tachycardia remodeling (ATR). ATR is thought to play a major role in the self-perpetuating nature of atrial fibrillation (AF) and has been a subject of intense research in large mammalian models of AF. Recently, rodents are increasingly used to gain insight on the pathophysiology AF. However, little is known regarding the effects of rapid pacing on the atria of rats and mice mainly due to technical challenges in electrophysiological studies of unanesthetized rodents. Using an implantable device for electrophysiological studies in unanesthetized rodents we examine, on a daily basis, the effects of continuous rapid atrial pacing (RAP) for at least 4 consecutive days on the developed AF substrate of Sprague-Dawley rats and C57BL6 mice. AF induction protocol consisted 10 aggressive bursts (20 seconds, double diastolic threshold, 10 ms cycle length [CL]). This protocol failed to induce AF at baseline in both species, but repeatedly induced AF episodes in rats following 2 days of sustained RAP. Microarray study of left atrial tissue from rats exposed for 2 days to RAP (70 ms CL) vs control pacing (140 ms CL) identified 304 differentially expressed genes (155 upregulated and 149 downregulated). Real-time qt-PCR confirmed the validity of the microarray. Enrichment analysis and comparison with a dataset of atrial tissue from AF patients revealed indications of increased carbohydrate metabolism, and changes in pathways that are thought to have critical role in human AF including TGF-beta and IL-6 signaling. Among 19 commonly affected genes in comparison with human AF, downregulation of FOXP1 and upregulation of the KCNK2 gene encoding the Kir2.1 potassium channel were conspicuous finding suggesting NFAT activation. Further results in line with NFAT activation included reduced expression of MIR-26, MIR-101, which were linked to upregulation of the KCNK2 in human AF. Our results demonstrate electrophysiological evidence for AF promoting effects of RAP in rats and some important molecular similarities between the effects of RAP in large and small mammalian models. The effects of atrial tachypacing are well documented in large mammals but very little is know regarding the effects of tacypacing on the rodent atria.

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A microRNA blueprint for early atrial remodeling in a porcine model of paroxysmal atrial fibrilation

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