Shortening Of Atrial Effective Refractory Period Research Articles

Pharmacological inhibition of acetylcholine-regulated potassium current (I K,ACh) prevents atrial arrhythmogenic changes in a rat model of repetitive obstructive respiratory events.

BackgroundIn obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase atrial fibrillation (AF) susceptibility by cholinergic activation.ObjectiveTo investigate short-term atrial electrophysiological consequences of obstructive respiratory events, simulated by intermittent negative upper airway pressure (INAP), and the role of atrial acetylcholine-regulated potassium current (IK,ACh) activated by the M2 receptor.MethodsIn sedated (2% isoflurane), spontaneously breathing rats, INAP was applied noninvasively by a negative pressure device for 1 minute, followed by a resting period of 4 minutes. INAP was applied repeatedly throughout 70 minutes, followed by a 2-hour recovery period. Atrial effective refractory period (AERP) and AF inducibility were determined throughout the protocol. To study INAP-induced IK,ACh activation, protein levels of protein kinase C (PKCƐ) were determined in membrane and cytosolic fractions of left atrial (LA) tissue by Western blotting. Moreover, an IK,ACh inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 μg/kg) were investigated.ResultsIn vehicle-treated rats, repetitive INAP shortened AERP (37 ± 3 ms vs baseline 44 ± 3 ms; P = .001) and increased LA membrane PKCƐ content relative to cytosolic levels. Upon INAP recovery, ratio of PKCƐ membrane to cytosol content normalized and INAP-induced AERP shortening reversed. Both XAF-1407 and atropine increased baseline AERP (control vs XAF-1407: 61 ± 4 ms; P > .001 and control vs atropine: 58 ± 3 ms; P = .011) and abolished INAP-associated AERP shortening.ConclusionShort-term simulated OSA is associated with a progressive, but transient, AERP shortening and a PKCƐ translocation to LA membrane. Pharmacological IK,ACh and muscarinic receptor inhibition prevented transient INAP-induced AERP shortening, suggesting an involvement of IK,ACh in the transient arrhythmogenic AF substrate in OSA.

Small conductance calcium activated K+ channel inhibitor decreases stretch induced vulnerability to atrial fibrillation.

BackgroundAtrial dilation is an important risk factor for atrial fibrillation (AF) and animal studies have found that acute atrial dilation shortens the atrial effective refractory period (AERP) and increases the risk of AF. Stretch activated ion channels (SACs) and calcium channels play a role in this. The expression profile and calcium dependent activation makes the small conductance calcium activated K+ channel (KCa2.x) a candidate for coupling stretch induced increases in intracellular calcium through K+-efflux and thereby shortening of atrial refractoriness.ObjectivesWe hypothesized that KCa2.x channel inhibitors can prevent the stretch induced shortening of AERP and protect the heart from AF.MethodsThe effect of KCa2 channel inhibitor (N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) 1 µM) was investigated using the isolated perfused rabbit heart preparation. To stretch the left atrium (LA) a balloon was inserted and inflated. AERP and action potential duration (APD) were recorded before and after atrial stretch. AF was induced by burst pacing the LA at different degrees of atrial stretch.ResultsStretching of the LA by increasing the balloon pressure from 0 to 20 mmHg shortened the AERP by 8.6 ± 1 ms. In comparison, the KCa2 inhibitor ICA significantly attenuated the stretch induced shortening of AERP to 2.5 ± 1.1 ms. Total AF duration increased linearly with atrial balloon pressure. This relationship was not found in the presence of ICA. ICA lowered the incidence of AF induction and total AF duration.ConclusionThe KCa2 channel inhibitor ICA attenuates the acute stretch induced shortening of AERP and decreases stretch induced vulnerability to AF.

Pharmacological inhibition of acetylcholine-regulated potassium current (IK,ACh) and associated A1- and M2-pathways prevent atrial arrhythmogenic changes in a rat model for obstructive sleep apnea

Abstract Background In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase vagal tone and adenosine release, potentially resulting in an increased acetylcholine-regulated potassium current (IK,ACh). Here we elucidated acute atrial electrophysiological effects of obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) and the role of atrial IKACh activation by A1-receptor and M2-receptor activation. Methods In sedated spontaneously breathing rats (2% isoflurane), either IK,ACh-inhibitor (XAF-1407: 1mg/kg), M2-receptor inhibitor (atropine; 1μg/kg), A1-receptor inhibitor (Rolofylline; 1μg/kg) or a buffer-based vehicle was perfused (Control). INAP was applied non-invasively by a negative pressure device 14 times throughout 70 minutes. Simulated apneas were maintained for one minute with a four minute resting period. Atrial effective refractory period (AERP) and atrial activation time were acquired by a programmed atrial pacing protocol before, during and after applied INAP throughout the study. Results Independent of IK,Ach-inhibition, single INAP applications prolonged transiently atrial activation times (Control: INAP vs. pre-INAP p=0.034; XAF-1407: INAP vs. pre-INAP p=0.039). In control-rats, seventy minutes of repetitive INAP decreased AERP by 15.45±0.06% (vs. baseline p=0.0015), which was reversible upon 1 hour of recovery. AERP shortening correlated with the cumulative pressure applied per body weight (Pearson r=−0.773; p=0.025). Whilst only XAF-1407 and atropine increased baseline AERP, all drug interventions, XAF-1407, atropine and Rolofylline could prevent INAP-associated AERP shortening (end INAP-protocol vs. respective baseline XAF-1407 p=0.994; atropine p=0.984; Rolofylline p=0.951). Drops in oxygen saturation and applied INAP were comparable in all groups. Conclusion Short-term simulated OSA is associated with progressive AERP shortening, which was determined by the cumulative negative airway pressure applied. This potentially represents an important insight in future OSA treatment. Pharmacological IK,ACh inhibition prevented INAP-associated AERP-shortening suggesting an involvement in acute atrial arrhythmogenesis in OSA. However, if IK,Ach and its potential upstream activating A1- and M2-pathway pose a pharmacological treatment target for OSA-patients with AF, requires further investigation. Funding Acknowledgement Type of funding source: None

741Pharmacological inhibition of the acetylcholine-regulated potassium channel (IK,ACh) prevents atrial arrhythmogenic changes in a rat model for obstructive sleep apnea

Abstract Background In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase vagal tone, resulting in an increased acetylcholine-regulated potassium current (IK,ACh). Here we elucidated acute atrial electrophysiological effects of obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) and the role of atrial IKACh activation. Methods In sedated spontaneously breathing rats (2% isoflurane), either IK,ACh-inhibitor (XAF-1407: 1mg/kg) or a buffer-based vehicle was perfused (Control). INAP was applied non-invasively by a negative pressure device 14 times throughout 70 minutes. Simulated apneas were maintained for one minute with a four minute resting period. Atrial effective refractory period (AERP), inducible atrial fibrillation (AF)-durations and atrial activation time were acquired by a programmed atrial pacing protocol before, during and after applied INAP throughout the study. Results During single INAP applications atrial activation times prolonged transiently in both groups (Control: INAP vs. pre-INAP p = 0.034; XAF-1407: INAP vs. pre-INAP p = 0.039). In control-rats, seventy minutes of repetitive INAP prolonged P-wave duration (+10.8 ± 2.7% vs. baseline, p = 0.008) and decreased AERP by 14.6 ± 3.1% (vs. baseline p = 0.001). AERP shortening correlated with the cumulative pressure applied per body weight (Pearson r= -0.773; p= 0.025). XAF-1407 could prevent P-wave prolongation and AERP shortening. Inducible AF-durations (CTR 0.94 ± 0.34s vs. XAF-1407 0.1 ± 0.09s p = 0.049) were shorter in XAF-1407 treated rats. Drops in oxygen saturation or applied INAP were comparable in control and XAF-1407 rats. Conclusion Short-term simulated OSA is associated with AF-related arrhythmogenic changes, which could be prevented by pharmacological IK,ACh inhibition. Moreover, the cumulative negative airway pressure applied determined aERP shortening and may represent a target for OSA treatment. These findings have important implications for the antiarrhythmic management of AF patients with OSA.

Role of intermediate-conductance calcium-activated potassium channels in atrial fibrillation in canines with rapid atrial pacing.

The aim of the present study was to explore the role of intermediate-conductance Ca2+-activated K+ (SK4) in atrial fibrillation (AF) inducibility in canines with rapid atrial pacing. Eighteen dogs were divided into the control group, the pacing group and the stellate ganglion ablation (SGA) + pacing group. In the pacing group, dogs were subjected to rapid atrial pacing, and the atrial effective refractory period (AERP) and AF inducibility were measured. After cessation of 7-h pacing, SK4 inhibitor (TRAM-34) was administered. After SGA, the SGA + pacing group received the same procedure of pacing and electrophysiological measurement as the pacing group. The expression of SK4 was measured in the left atrium (LA) and the right atrium (RA) in the three groups. The duration of the AERP decreased, while the number of AF episodes, the duration of induced AF, and the amplitude of stellate ganglion neural activity all increased after rapid atrial pacing. TRAM-34 completely inhibited AF induction in the pacing group. There was no significant difference in AERP shortening or AF vulnerability between the SGA + pacing group and the control group. The expression of SK4 in the LA and RA was higher in the pacing group than in the control and SGA + pacing groups. However, there was no significant difference in the expression of SK4 in the LA or the RA between the SGA + pacing group and the control group. The higher expression of SK4 plays an important role in AF induction and the increased expression of SK4 in the atrium is related to SG activity during rapid atrial pacing.

Alterations in atrial ion channels and tissue structure promote atrial fibrillation in hypothyroid rats.

It is well known that hyperthyroidism is associated with atrial fibrillation (AF); however, the relationship between hypothyroidism and AF remains controversial. Hypothyroidism was established in rats by two methods: methimazole-induced (MMI) and thyroidectomy (TX). MMI model includes control (n = 10), MMI (n = 10), and MMI + L-thyroxine (T4, n = 10). Methimazole was given intragastrically in MMI and MMI + T4 for 12 weeks, and T4 was added intragastrically in MMI + T4 at week 5. TX model includes sham (n = 10), TX (n = 10), and TX + T4 (n = 10). Four weeks after surgery, rats in TX + T4 received T4 for 8 weeks. Triiodothyronine (T3), T4, and thyroid-stimulating hormone (TSH) were measured. Electrophysiology, tissue structure and function, and protein levels of potassium and L-type calcium channels were assessed in the atria. Severe changes in the atrial structure of hypothyroid rats were observed. Compared with euthyroid rats, atrial effective refractory period (AERP) in hypothyroid rats was significantly shortened; accordingly, inducibility and duration of AF were considerably increased. Protein levels of minK, Kv1.5, Kv4.2, Kv4.3, Kv7.1, and Cav1.2 were upregulated in hypothyroid rats, whereas there was only a tendency toward increased Kir2.1. Kv11.1 was statistically upregulated in the MMI model and had an increasing tendency in the TX model. Conversely, Kir3.1 and Kir3.4 were downregulated in hypothyroid rats. The above changes could be partially inhibited by T4 treatment. AERP shortening due to altered protein levels of ion channels and atrial structural changes increased the susceptibility to AF in hypothyroidism. Thyroid replacement therapy could prevent electrical and structural remodeling under hypothyroid condition.

Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation.

Atrial fibrillation (AF) is frequently associated with enhanced inflammatory response. The NLRP3 (NACHT, LRR, and PYD domain containing protein 3) inflammasome mediates caspase-1 activation and interleukin-1β release in immune cells but is not known to play a role in cardiomyocytes (CMs). Here, we assessed the role of CM NLRP3 inflammasome in AF. NLRP3 inflammasome activation was assessed by immunoblot in atrial whole-tissue lysates and CMs from patients with paroxysmal AF or long-standing persistent (chronic) AF. To determine whether CM-specific activation of NLPR3 is sufficient to promote AF, a CM-specific knockin mouse model expressing constitutively active NLRP3 (CM-KI) was established. In vivo electrophysiology was used to assess atrial arrhythmia vulnerability. To evaluate the mechanism of AF, electric activation pattern, Ca2+ spark frequency, atrial effective refractory period, and morphology of atria were evaluated in CM-KI mice and wild-type littermates. NLRP3 inflammasome activity was increased in the atrial CMs of patients with paroxysmal AF and chronic AF. CM-KI mice developed spontaneous premature atrial contractions and inducible AF, which was attenuated by a specific NLRP3 inflammasome inhibitor, MCC950. CM-KI mice exhibited ectopic activity, abnormal sarcoplasmic reticulum Ca2+ release, atrial effective refractory period shortening, and atrial hypertrophy. Adeno-associated virus subtype-9-mediated CM-specific knockdown of Nlrp3 suppressed AF development in CM-KI mice. Finally, genetic inhibition of Nlrp3 prevented AF development in CREM transgenic mice, a well-characterized mouse model of spontaneous AF. Our study establishes a novel pathophysiological role for CM NLRP3 inflammasome signaling, with a mechanistic link to the pathogenesis of AF, and establishes the inhibition of NLRP3 as a potential novel AF therapy approach.

Selective ablation of the ligament of Marshall attenuates atrial electrical remodeling in a short-term rapid atrial pacing canine model.

Cardiac sympathetic activation facilitates atrial electrical remodeling during atrial fibrillation (AF). Selective ablation of the distal part of the ligament of Marshall (LOMLSPV ) could decrease cardiac sympathetic innervation. This study aimed to investigate the effects of LOMLSPV ablation on atrial electrical remodeling in a short-term rapid atrial pacing (RAP) model. In 16 anesthetized dogs, 6hours of RAP (20Hz, 2 × threshold) was delivered before LOMLSPV ablation (group 1, N=8) or after (group 2, N=8). Heart rate variability (HRV), serum norepinephrine (NE), atrial electrophysiological indices were analyzed. Six times of burst pacing (20Hz, 2 × threshold, lasting for 5 seconds, were performed to induce AF, the number of episodes and the duration of AF were compared. LOMLSPV ablation decreased sympathetic indices of HRV and serum NE. Atrial effective refractory period (ERP) was shortened during RAP in both groups with higher reduction degrees in group 1. In group 1, the shortening of atrial ERP, elevating of ERP dispersion and sum of window of vulnerability (ΣWOV), facilitating of AF induced by RAP were subsequently reversed by LOMLSPV ablation. In group 2, LOMLSPV ablation prolonged atrial ERP, decreased ΣWOV, eliminated AF induction. The subsequent RAP failed to alter these indices. Histological studies showed abundant sympathetic nerve fibers in LOMLSPV . LOMLSPV ablation could inhibit atrial electrical remodeling during short-term RAP by reducing the cardiac sympathetic activity. LOMLSPV may be a potential target in AF ablation, especially in patients with highly cardiac sympathetic activation or atrial electrical remodeling.

Linagliptin prevents atrial electrical and structural remodeling in a canine model of atrial fibrillation.

Dipeptidyl peptidase 4 (DPP-4) inhibitors have recently been reported to exhibit additional cardioprotective effects; however, their effect in atrial remodeling, such as in atrial fibrillation (AF), remains unclear. In this study, the effect of linagliptin on atrial electrical and structural remodeling was evaluated in a canine AF model. Sixteen beagle dogs with 3-week atrial rapid stimulation were divided into the linagliptin group (9mg/kg/day, n = 8) and pacing control group (n = 8). Three additional dogs without rapid pacing were assigned into non-pacing group, which was used as sham in this study. In the dogs with rapid pacing, the atrial effective refractory period (AERP), conduction velocity (CV), and AF inducibility were evaluated and blood was sampled every week. After the entire protocol, atrial tissue was sampled for histological examinations using HE, Azan, and dihydroethidium (DHE) staining to evaluate any tissue damage or oxidative stress. The pacing control group exhibited a gradual AERP shortening and CV decrease along the time course as previously reported. In the linagliptin group, the AERP shortening was not affected, but the CV decrease was suppressed in comparison to the control group (p < 0.05). The AF inducibility was increased in the control group and suppressed in the linagliptin group (p < 0.05). The control group exhibited tissue fibrosis, the degree of which was suppressed in the linagliptin group. DHE staining exhibited suppression of the reactive oxygen species expression in the linagliptin group in comparison to the pacing control group. Linagliptin, a DPP-4-inhibitor, suppressed the AF inducibility, CV decrease, and overexpression of oxidative stress in the canine AF model. Such suppressive effects of linagliptin on AF in the canine model may possibly be related to the anti-oxidative effect.

Effect of botulinum toxin on inducibility and maintenance of atrial fibrillation in ovine myocardial tissue

Aberrant vagal stimulation may promote the generation and propagation of atrial fibrillation (AF). Researchers have suggested that botulinum toxin (BTX), a neurotoxin that decreases neural vagal stimulation, may decrease the incidence of postoperative AF. The exact electrophysiologic mechanism underlying the observations and histopathologic alterations associated with BTX are unclear. To investigate the electrophysiologic, functional, and histopathologic effects of BTX on fibrillation induction in ovine atria. Eight sheep underwent BTX injections into their pulmonary veins, atrial fat pads, and ventricular walls. Electrophysiology with pacing was performed at baseline and 7 days after injection to evaluate the atrial effective refractory period (ERP) and vulnerability to AF with and without vagal stimulation. Echocardiography was performed at baseline and day 7. After euthanasia, histopathologic analysis was performed. Seven sheep completed the study. For both atria, there was significant shortening in the ERP with vagal stimulation versus no stimulation on day 0 but not on day 7. More aggressive pacing was required to induce AF in the left atrium on day 7 than on day 0. Echocardiography on day 7 showed no significant changes in ejection fraction or new wall-motion abnormalities of the left and right ventricle. Histopathologic analysis showed no significant adverse effects. The subacute BTX effect reduced the vulnerability of atrial tissue to AF induction and reduced the vagal influence on atrial ERP shortening compared to baseline levels. Direct BTX injection did not cause myocardial dysfunction or histologic adverse effects.

The potential role of atrial natriuretic peptide in the effects of Angiotensin-(1-7) in a chronic atrial tachycardia canine model.

Objective:The objective of this article is to investigate the possible role of atrial natriuretic peptide (ANP) in Angiotensin-(1–7) (Ang-(1–7)) signaling pathway on atrial electrical and structural remodeling in a chronic rapid atrial pacing canine model.Methods:Twenty-four dogs were randomly assigned to four groups: a sham group, paced control group, a paced + Ang-(1–7) group and a paced + Ang-(1–7) + A-71915 group. Atrial rapid pacing (ARP) at 600 bpm was maintained for 14 days except in the animals from the sham group. During the pacing, Ang-(1–7) (6 μg•kg-1•h-1) or Ang-(1–7) (6 μg•kg-1•h-1) + A-71915 (ANP receptor antagonist, 0.30 μg•kg-1•h-1) were given intravenously, respectively. After pacing, it was measured that electrophysiological parameters including atrial effective refractory periods (ERPs), inducibility and duration of atrial fibrillation (AF), ICaL and INa changed, where ICaL refers to voltage-dependent L-type Ca2+ current and INa refers to cardiac sodium current. Then, the fibrosis and the expression of Cav1.2, INav1.5α subunit, TGF-β1 and ANP in atria were assessed.Results:After ARP, compared with the sham group, the atrial ERPs at six sites in each dog were shortened with the increasing in inducibility and duration of AF in the paced control group. The density of ICaL, INa and the expression of Cav1.2, INav1.5α subunit mRNA were decreased. Atrial tissue from the paced dogs showed significant interstitial fibrosis. The expression of TGF-β1 and ANP in mRNA and protein levels were increased. Compared with the paced control group, the shortening of atrial ERPs, and the increasing of inducibility and duration of AF induced by ARP were alleviated by Ang-(1–7) treatment (p < 0.05). The density of ICaL and INa and the expression of Cav1.2 and INav1.5α subunit mRNA were slightly decreased. Atrial tissue showed less interstitial fibrosis after Ang-(1–7) treatment. The increasing of ANP expression was improved by Ang-(1–7), while the increasing of TGF-β1 expression was alleviated by Ang-(1–7) (p < 0.05). A-71915 treatment blocked the beneficial effects of Ang-(1–7) on the aforementioned electrophysiological parameters and atrial fibrosis. And A-71915 treatment blocked Ang-(1–7), improving the expression of TGF-β1.Conclusion:Ang-(1–7) prevented atrial structural and electrical remodeling induced by ARP. Furthermore, Ang-(1–7) promoted ANP secretion, and ANP played a crucial role in the cardiac protection of the former.

Effects of low-intensity autonomic nerve stimulation on atrial electrophysiology.

Background and ObjectivesThe cardiac autonomic nervous system is an emerging target for therapeutic control of atrial fibrillation (AF). We evaluated the effects of low-intensity autonomic nerve stimulation (LI-ANS) on atrial electrophysiology, AF vulnerability, and neural remodeling.Subjects and MethodsFourteen dogs were subjected to 3 hours rapid atrial pacing (RAP, 5 Hz) and concomitant high frequency LI-ANS (20 Hz, at voltages 40% below the threshold) as follows: no autonomic stimulation (control, n=3); or right cervical vagus nerve (RVN, n=6), anterior right ganglionated plexi (ARGP, n=3), and superior left ganglionated plexi (SLGP, n=2) stimulation. Programmed and burst atrial pacing were performed at baseline and at the end of each hour to determine atrial effective refractory period (ERP), window of vulnerability (WOV), and inducibility of sustained AF.ResultsAtrial ERP was significantly shortened by 3 hours RAP (in control group, ΔERP=-47.9±8.9%, p=0.032), and RAP-induced ERP shortening was attenuated by LI-ANS (in LI-ANS group, ΔERP=-15.4±5.9%, p=0.019; vs. control, p=0.035). Neither WOV for AF nor AF inducibility changed significantly during 3 hours RAP with simultaneous LI-ANS. There was no significant difference between the control and LI-ANS group in nerve density and sprouting evaluated by anti-tyrosine hydroxylase and anti-growth associated protein-43 staining. Among the various sites for LI-ANS, the ARGP-stimulation group showed marginally lower ΔWOV (p=0.077) and lower nerve sprouting (p=0.065) compared to the RVN-stimulation group.ConclusionLow-intensity autonomic nerve stimulation significantly attenuated the shortening of atrial ERP caused by RAP. ARGP may be a better target for LI-ANS than RVN for the purpose of suppressing atrial remodeling in AF.

MicroRNA-1 Accelerates the Shortening of Atrial Effective Refractory Period by Regulating KCNE1 and KCNB2 Expression: An Atrial Tachypacing Rabbit Model

BackgroundThe potential mechanisms of microRNA-1 (miR-1) in the electrical remodeling of atrial fibrillation remain unclear. The purpose of this study was to evaluate the effects of miR-1 on the atrial effective refractory period (AERP) in a right atrial tachypacing model and to elucidate the potential mechanisms.Methods and ResultsQRT-PCR and western blot were used to detect the expression of the miR-1, KCNE1, and KCNB2 genes after 1-week of right atrial tachypacing in New Zealand white rabbits. The AERP was measured using a programmable multichannel stimulator, and atrial fibrillation was induced by burst stimulation in vivo. The slowly activating delayed rectifier potassium current (IKs) and AERP in atrial cells were measured by whole cell patch clamp in vitro. Right atrial tachypacing upregulated miR-1 expression and downregulated KCNE1 and KCNB2 in this study, while the AERP was decreased and the atrial IKs increased. The downregulation of KCNE1 and KCNB2 levels was greater when miR-1 was further upregulated through in vivo lentiviral infection. Electrophysiological tests indicated a shorter AERP, a great increase in the IKs and a higher atrial fibrillation inducibility. In addition, similar results were found when the levels of KCNE1 and KCNB2 were downregulated by small interfering RNA while keeping miR-1 level unaltered. Conversely, knockdown of miR-1 by anti-miR-1 inhibitor oligonucleotides alleviated the downregulation of KCNE1 and KCNB2, the shortening of AERP, and the increase in the IKs. KCNE1 and KCNB2 as the target genes for miR-1 were confirmed by luciferase activity assay.ConclusionsThese results indicate that miR-1 accelerates right atrial tachypacing-induced AERP shortening by targeting potassium channel genes, which further suggests that miR-1 plays an important role in the electrical remodeling of atrial fibrillation and exhibits significant clinical relevance as a potential therapeutic target for atrial fibrillation.

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Effects of Electrical Stimulation of Carotid Baroreflex and Renal Denervation on Atrial Electrophysiology

This study was designed to compare the effect of electrical baroreflex stimulation (BRS) at an intensity used in hypertensive patients and renal denervation (RDN) on atrial electrophysiology. BRS and RDN reduce blood pressure and global sympathetic drive in patients with resistant hypertension. Whereas RDN decreases sympathetic renal afferent nerve activity, leading to decreased central sympathetic drive, BRS modulates autonomic balance by activation of the baroreflex, resulting in both reduced sympathetic drive and increased vagal activation. Increased vagal tone potentially shortens atrial refractoriness resulting in a stabilization of reentry circuits perpetuating atrial fibrillation (AF). In normotensive anesthetized pigs (n = 12), we compared the acute effect of BRS and RDN on blood pressure, atrial effective refractory period (AERP), and inducibility of AF. Electrical BRS was titrated to result in comparable heart rate and blood pressure reduction compared to irreversible RDN. BRS resulted in a rapid and pronounced shortening of AERP (from 162 ± 8 milliseconds to 117 ± 16 milliseconds, P = 0.001) associated with increased AF-inducibility from 0% to 82%. This shortening in AERP was completely reversible after stopping BRS. After administration of atropine, AF-inducibility during BRS was attenuated. Ventricular repolarization was not modulated by BRS. In RDN, AF was not inducible; however, it did not prevent BRS-induced shortening of AERP. RDN and BRS resulting in comparable blood pressure and heart rate reductions differently influence atrial electrophysiology. Vagally mediated shortening of AERP, resulting in increased AF-inducibility, was observed with BRS but not with RDN.

Renal Sympathetic Denervation Suppresses Postapneic Blood Pressure Rises and Atrial Fibrillation in a Model for Sleep Apnea

The aim of this study was to identify the relative impact of adrenergic and cholinergic activity on atrial fibrillation (AF) inducibility and blood pressure (BP) in a model for obstructive sleep apnea. Obstructive sleep apnea is associated with sympathovagal disbalance, AF, and postapneic BP rises. Renal denervation (RDN) reduces renal efferent and possibly also afferent sympathetic activity and BP in resistant hypertension. The effects of RDN compared with β-blockade by atenolol on atrial electrophysiological changes, AF inducibility, and BP during obstructive events and on shortening of atrial effective refractory period (AERP) induced by high-frequency stimulation of ganglionated plexi were investigated in 20 anesthetized pigs. Tracheal occlusion with applied negative tracheal pressure (NTP; at -80 mbar) induced pronounced AERP shortening and increased AF inducibility in all of the pigs. RDN but not atenolol reduced NTP-induced AF-inducibility (20% versus 100% at baseline; P=0.0001) and attenuated NTP-induced AERP shortening more than atenolol (27±5 versus 43±3 ms after atenolol; P=0.0272). Administration of atropine after RDN or atenolol completely inhibited NTP-induced AERP shortening. AERP shortening induced by high-frequency stimulation of ganglionated plexi was not influenced by RDN, suggesting that changes in sensitivity of ganglionated plexi do not play a role in the antiarrhythmic effect of RDN. Postapneic BP rise was inhibited by RDN and not modified by atenolol. We showed that vagally mediated NTP-induced AERP shortening is modulated by RDN or atenolol, which emphasizes the importance of autonomic disbalance in obstructive sleep apnea-associated AF. Renal denervation displays antiarrhythmic effects by reducing NTP-induced AERP shortening and inhibits postapneic BP rises associated with obstructive events.

Combined blockade of early and late activated atrial potassium currents suppresses atrial fibrillation in a pig model of obstructive apnea

Negative tracheal pressure (NTP) during tracheal obstruction in obstructive apnea increases vagal tone and causes pronounced shortening of the atrial effective refractory period (AERP), thereby perpetuating atrial fibrillation (AF). The role of different atrial potassium channels under those conditions has not been investigated. The purpose of this study was to evaluate the atrial effects of blockade of the late activated potassium current (I(Kr)) by sotalol, of blockade of the early activated potassium currents (I(Kur)/I(to)) by AVE0118, and of the multichannel blocker amiodarone during tracheal occlusions with applied NTP. Twenty-one pigs were anesthetized, and an endotracheal tube was placed to apply NTP (up to -100 mbar) comparable to clinically observed obstructive sleep apnea for 2 minutes. Right AERP and AF inducibility were measured transvenously by a monophasic action potential recording and stimulation catheter. Tracheal occlusion with applied NTP caused pronounced AERP shortening. AF was inducible during all NTP maneuvers. Blockade of I(Kr) by sotalol, blockade of I(Kur)/I(to) by AVE0118, and amiodarone did not affect NTP-induced AERP shortening, although they prolonged the AERP during normal breathing. Atropine given after amiodarone completely inhibited NTP-induced AERP shortening. The combined blockade of I(Kr) and I(Kur)/I(to) by sotalol plus AVE0118, however, attenuated NTP-induced AERP shortening and AF inducibility independent of the order of administration. The atrial proarrhythmic effect of NTP simulating obstructive apneas is difficult to inhibit by class III antiarrhythmic drugs. Neither amiodarone nor blockade of I(Kr) or I(Kur)/I(to) attenuated NTP-induced AERP shortening. However, the combined blockade of I(Kur)/I(to) and I(Kr) suppressed NTP-induced AERP shortening.

Nitric oxide delays atrial tachycardia-induced electrical remodelling in a sheep model

Rapid atrial pacing for 1 week leads to decreased expression of endocardial nitric oxide (NO)-synthase and decreased NO concentrations. We hypothesized that increasing NO bioavailability may reduce electrical remodelling induced by atrial tachycardia. We examined the effect of molsidomine, a NO donor, and N(ω)-nitro-l-arginine methylester (l-NAME), a NO-synthase inhibitor, on electrical remodelling occurring during 4 h of rapid atrial pacing in sheep. Haemodynamic and electrophysiological parameters were measured at baseline, 1 h after the start of the infusion and before the start of pacing, and 2 and 4 h after pacing. We measured the effect of molsidomine on atrial monophasic action potentials (MAPs) in non-instrumented sheep and on l-type Ca(2+) currents and intracellular Ca(2+) concentration ([Ca(2+)](i)) transients in right atrial cells, isolated from control sheep. In control sheep, rapid atrial pacing shortened the atrial effective refractory period (AERP) by 12 ± 0.18% after 4 h, an effect that was unaffected by l-NAME. Infusion of molsidomine increased AERP at baseline (+13.4 ± 1.04%) and transiently attenuated pacing-induced AERP shortening (13.6 ± 0.1% at 2 h). Molsidomine tended to increase MAP duration by 20.7 ± 13.4 ms. Incubation of isolated atrial myocytes with NO donor 3-morpholino-sydnonimine (SIN-1) increased significantly l-type Ca(2+) current and [Ca(2+)](i) transients. Infusion of molsidomine, a NO donor, delayed shortening of the action potential during short-term rapid atrial pacing, by increasing [Ca(2+)](i). Whereas the former could be protective against repetitive short episodes of atrial fibrillation, the latter might be detrimental in the long term.

Anti-Arrhythmic Action of an ATP-Sensitive Potassium Channel Blocker Against Atrial Fibrillation Associated with Beta-Adrenergic Stress in Rat Hearts

Atrial fibrillation (AF) is the most common disturbance of cardiac rhythm and results in a significantly increased risk of death. Although it is widely accepted that changes to the atrial muscle associated with heart disease make prolonged episodes of AF more likely to occur, the mechanisms underlying the origins of AF remain unclear. It is thought that sympathetic innervation plays an important role in the initiation of paroxysms of AF. ATP-sensitive K+ channels (KATP channels) have been suggested to contribute to myocardial responses to beta-adrenergic stress. To investigate the role of KATP channel opening in the genesis of AF associated with beta-adrenergic stress, we examined the susceptibility to AF of excised Langendorff-perfused hearts from adult male Wistar rats. Unipolar electrograms were recorded from the left atrial epicardial surface of perfused hearts using a multi-electrode array, allowing measurements of atrial effective refractory period (AERP) and conduction velocity (CV) through the construction of activation maps. Paroxysms of AF were induced by burst pacing and the incidence and duration of the arrhythmia noted. Beta-adrenergic stress was induced by perfusion of the hearts with isoprenaline (ISO). While it was not possible to induce paroxysms of AF in control conditions, perfusion of the hearts with ISO rendered the left atrium susceptible to pacing-induced AF; the incidence and duration of which increased in a concentration-dependent manner. The shortening of AERP and incidence of AF induced by 10−6 M ISO were completely blocked in the presence of the KATP channel blocker, glibenclamide (10−5 M). In the absence of ISO, glibenclamide had no effect on AERP or CV. Taken together, our results suggest that KATP channels can contribute to atrial arrhythmogenesis during beta-adrenergic stress.Supported by the BHF (PG/09/046).

Direct Renin Inhibitor Suppresses the Atrial Remodeling and AF Inducibility in the Canine AF Model

Background: Although several experimental studies have exhibited possibility of angiotensin receptor blocker as the upstream therapy for atrial fibrillation (AF), plural clinical trials have questioned about its effect. The mechanism of this discrepancy might be explained by in-balanced suppression of the renin-angiotensin system such as aldosterone breakthrough phenomenon, and direct renin inhibitor (aliskiren) is expected to achieve balanced suppression. We evaluated the effect of aliskiren on AF in the canine AF model. Methods: 9 dogs with atrial rapid stimulation were divided into 2 groups; 1) aliskiren group (n=5): rapid atrial pacing for 6 weeks with aliskiren (30 mg/kg/day), and 2) control group (n=4): rapid pacing without any medication. Atrial effective refractory period (AERP), conduction velocity (CV), AF inducibility were evaluated in every week during the 6 week protocol. Results: The control group exhibited gradual AERP shortening and CV decrease along the time course as previously reported. In the aliskiren group, AERP shortening was not affected, but CV decrease was suppressed in comparison with the control. The AF inducibility was gradually increased in the control, but it was suppressed in the aliskiren group (p<0.05). Conclusions: Aliskiren suppressed the increase of AF inducibility and decrease in CV in the canine AF model. Aliskiren might be a possible tool for the upstream therapy for AF.