vasoactive-intestinal-peptide and Atrial-Fibrillation

Neuropeptide levels are closely associated with the development and maintenance of atrial fibrillation (AF) after myocardial infarction (MI). This study was aimed at investigating the regulatory network that affects neuropeptide expression through transcription factor modulation.. We downloaded three datasets from the GEO database, and after performing differential and crosstabulation analyses, we screened out differentially expressed (DE) miRNAs and DEmRNAs coexpressed in AF and MI and performed DEmiRNA-DEmRNA pairing prediction; from which, we constructed a regulatory network. Subsequently, the hsa-miR-662-CREB1-VIP axis was obtained, and the role of CREB1 and VIP in the development of AF after MI was further revealed by single-cell analysis and prediction model construction.. In this study, eight DEmRNAs and four miRNAs were screened. hsa-miR-662 was identified by database integration analysis to regulate the transcription factor CREB1, a potential transcriptional regulator in VIP. CREB1 and VIP are mainly enriched in pathways of energy metabolism, ion channels, and myocardial contraction. CREB1 and VIP were identified as biomarkers of the onset and prognosis of MI and AF.. In this study, the miR-662/CREB1/VIP regulatory pathway was constructed through integrated analysis of datasets, thus providing new ideas to study the mechanisms of AF development.

Topics: Aged; Atrial Fibrillation; Biomarkers; Case-Control Studies; Computational Biology; Cyclic AMP Response Element-Binding Protein; Electrophysiology; Female; Follow-Up Studies; Gene Expression Regulation; Humans; Infarction; Male; MicroRNAs; Prognosis; Vasoactive Intestinal Peptide

Vagal hyperactivity promotes atrial fibrillation (AF), which has been almost exclusively attributed to acetylcholine. Vasoactive intestinal polypeptide (VIP) and acetylcholine are neurotransmitters co-released during vagal stimulation. Exogenous VIP has been shown to promote AF by shortening action potential duration (APD), increasing APD spatial heterogeneity, and causing intra-atrial conduction block.. The purpose of this study was to investigate the effects of neuronally released VIP on atrial electrophysiologic properties during vagal stimulation.. We used a specific VIP antagonist (H9935) to uncover the effects of endogenous VIP released during vagal stimulation in canine hearts.. H9935 significantly attenuated (1) the vagally induced shortening of atrial effective refractory period and widening of atrial vulnerability window during stimulation of cervical vagosympathetic trunks (VCNS) and (2) vagal effects on APD during stimulation through fat-pad ganglion plexus (VGPS). Atropine completely abolished these vagal effects during VCNS and VGPS. In contrast, VGPS-induced slowing of local conduction velocity was completely abolished by either VIP antagonist or atropine. In pacing-induced AF during VGPS, maximal dominant frequencies and their spatial gradients were reduced significantly by H9935 and, more pronouncedly, by atropine. Furthermore, VIP release in the atria during vagal stimulation was inhibited by atropine, which may account for the concealment of VIP effects with muscarinic blockade.. Neuronally released VIP contributes to vagal effects on atrial electrophysiologic properties and affects the pathophysiology of vagally induced AF. Neuronal release of VIP in the atria is inhibited by muscarinic blockade, a novel mechanism by which VIP effects are concealed by atropine during vagal stimulation.

Topics: Action Potentials; Animals; Atrial Fibrillation; Atrial Function; Atropine; Dogs; Muscarine; Refractory Period, Electrophysiological; Vagus Nerve Stimulation; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP) is released from intracardiac neurons during vagal stimulation, ischemia, and heart failure, which are associated with increased vulnerability to atrial fibrillation. VIP shortens atrial effective refractory periods in dogs. Endogenous VIP contributes to vagally mediated acceleration of atrial electric remodeling. VIP is also shown to prolong the duration of acetylcholine-induced atrial fibrillation. However, the ionic mechanisms underlying VIP effects are largely unknown.. The effects of VIP on transmembrane ion channels were studied in canine atrial cardiomyocytes using patch-clamp techniques. VIP increased delayed rectifier K+ current and L-type calcium current but decreased the transient outward K+ current and sodium current. Optical mapping technique was used to assess effects of VIP on action potential durations (APDs) in isolated canine left atria. VIP shortened APD and slowed conduction velocity in a dose-dependent manner. Furthermore, VIP increased spatial heterogeneity of APD and conduction velocity, as assessed by the SDs of APD and conduction velocity, and atrial fibrillation inducibility.. Through its diverse effects on ion channels, VIP shortens APD with increased APD spatial heterogeneity and decreases intra-atrial conduction velocity, which may play an important role in the pathogenesis of atrial arrhythmias in scenarios where VIP release is increased.

Topics: Action Potentials; Animals; Atrial Fibrillation; Calcium Channels; Dogs; Heart Atria; Heart Conduction System; Myocytes, Cardiac; Patch-Clamp Techniques; Potassium Channels; Vasoactive Intestinal Peptide

We investigated the effects of a neuropeptide, pituitary adenylate cyclase-activating polypeptide- (PACAP) 27, on the sinoatrial nodal pacemaker activity and the mechanisms for the cardiac effects of PACAP-27 in the autonomically decentralized heart of the anesthetized dog. PACAP-27 (0.01-0.3 nmol) injected into the sinus node artery increased followed by decreased sinus rate. PACAP-27 (0.1 and 0.3 nmol) caused atrial fibrillation spontaneously. After atropine, PACAP-27 never decreased but only increased sinus rate as did vasoactive intestinal peptide. However, propranolol did not affect the negative and positive chronotropic effects. Tetrodotoxin but not hexamethonium abolished the negative chronotropic response to PACAP-27 in atropine nontreated dogs, and tetrodotoxin also inhibited the positive chronotropic response by 34% in atropine-treated dogs. In atropine- and propranolol-treated dogs, positive chronotropic responses to PACAP-27 were inhibited by PACAP-(6-27), a PACAP receptor antagonist but not by vasoactive intestinal peptide (10-28), a vasoactive intestinal peptide receptor antagonist. These results indicate that PACAP-27 causes the negative chronotropic effect through the postganglionic parasympathetic nerve activation and it produces the positive chronotropic effect mediated by PACAP receptors with an activation of non-adrenergic, nonvasoactive intestinal peptide-ergic nerves at least in part in the dog heart. Atropine and tetrodotoxin abolished atrial fibrillation induced by PACAP-27 but other blockers did not. These results suggest that neurally released acetylcholine induced by PACAP-27 participates in the induction of atrial fibrillation.

Topics: Anesthesia; Animals; Atrial Fibrillation; Atropine; Dogs; Female; Heart Rate; Hexamethonium; Male; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Propranolol; Sinoatrial Node; Tetrodotoxin; Vasoactive Intestinal Peptide