Copyright © 2005, European Society of Cardiology
Region-specific, pacing-induced changes in repolarization in rabbit atrium: An example of sensitivity to the rare
Center for Molecular Therapeutics, Department of Pharmacology and Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY, United States
* Corresponding author. College of Physicians and Surgeons of Columbia University, Department of Pharmacology, 630 West 168 Street, PH 7West-321, New York, NY 10032, United States. Tel.: +1 212 305 8754. fax: +1 212 305 8351. Email address: mrr1{at}columbia.edu
Received 1 February 2005; revised 24 March 2005; accepted 11 April 2005
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Objective: In subsets of patients paroxysmal firing of ectopic foci in pulmonary veins or coronary sinus is an important cause of atrial fibrillation. This appears to represent a rare event overriding a dominant sinus mechanism to alter the rhythmic firing of the atrium. Hence, we tested the hypothesis that a rare stimulation pattern might alter the myocardial substrate, making it more susceptible to the initiation of arrhythmias.
Methods: In isolated right and left rabbit atria, a "rare" burst pacing protocol (BPP) was applied as follows: over 3 h, preparations were driven for 4.5 min from sinus node (SN) or Bachmann's bundle (BB) regions at cycle length (CL)=400 ms followed by 30 s of stimulation from coronary sinus (CS) or pulmonary vein (PV) at CL=200 ms. Microelectrodes were used to record action potentials at the end of 4.5 min of pacing at CL=400 ms. We then intervened with 5-min bigeminal pacing to probe atrial vulnerability to arrhythmias: S1 was delivered from SN or BB and S2 from CS or PV, respectively. S1–S2 interval was the shortest eliciting a propagated response.
Results: BPP shortened repolarization in CS and PV regions but not in SN or BB, resulting in increased dispersion of repolarization in right and decreased in left atria. Propranolol, atropine and losartan failed to alter the decrease in repolarization induced by BPP whereas apamin, nifedipine and ryanodine prevented BPP effects. Before BPP, bigeminy did not induce arrhythmias in either atrium, but after BPP, bigeminy significantly increased the incidence of arrhythmias in the right atrium.
Conclusions: BPP from foci outside the regions of dominant activation alters dispersion of atrial repolarization. Modulation of apamin-sensitive channels may contribute to the shortening of repolarization in CS and PV regions. Alterations of atrial repolarization gradient create an arrhythmogenic substrate and may be an early step in atrial electrophysiologic remodeling.
KEYWORDS Arrhythmia (mechanism); Atrial function; Membrane potential; Repolarization
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Atrial fibrillation, one of the leading causes of arrhythmia induced disability, is often a progressive disease, evolving from paroxysmal through persistent through permanent expression [1–3]. In a subset of patients an important cause of atrial fibrillation is paroxysmal firing of ectopic foci in pulmonary veins [4,5] and coronary sinus [6,7]. This behavior might be considered as a rare event (the bursting focus) overriding a dominant sinus mechanism to alter the rhythmic firing of the atrium.
The scenario of a rare event overcoming a dominant rhythm has a counterpart in the activity expressed by some neuronal systems. Specifically, in cultured neural networks used to study learning, there may be multiple sites and rates of rhythmic activity, with one being dominant and others, rare. Increased repetition of a dominant rhythmic pattern via a pacing intervention has little effect to modify the overall rhythmicity of the culture, but stimulation to mimic rarely occurring patterns is highly effective in bringing them to dominance [8,9]. This phenomenon has been called "sensitivity to the rare" [8,9]. We recently hypothesized that a similar sensitivity to rare stimuli that alter atrial activation might help explain the effect of impulses originating in cardiac vessels to cause tachycardia/fibrillation in normal atria [10]. We based this hypothesis on two observations: (1) our own research indicating that atrial pacing at physiologic rates but from ectopic sites induces atrial electrophysiologic remodeling [11], atrial tachycardias and fibrillation [12], and (2) research by others indicating that bursting behavior in pulmonary veins and coronary sinus can initiate atrial fibrillation [4–7]. Both the pacing-induced arrhythmias and the ectopic activity in cardiac vasculature represent rare activity superimposed on the dominant activity characteristic of sinus rhythm. Therefore, we tested the hypothesis that a rare stimulation pattern might alter parts of the atrial myocardial substrate, making it more susceptible to the initiation of arrhythmias. The hypothesis was tested in isolated rabbit right and left atrial preparations. In testing this hypothesis, we were not suggesting that a phenomenon studied for 3 h in the laboratory was analogous to an arrhythmia that typically evolves over months to years in the clinic. Rather, we were asking whether brief periods of intervention such as those we used might reproducibly initiate a remodeling process that was compatible with arrhythmia initiation. This was important to us, as the processes initiating arrhythmias have not been studied in as much depth as those involved as triggers or perpetuators (e.g. [3]).
We also intervened pharmacologically, using propranolol and atropine to test whether changes seen might be autonomically modulated, losartan to assess a possible involvement of angiotensin II, nifedipine and ryanodine to explore Ca2+ modulation, and apamin to test the presence of a Ca2+-modulated potassium conductance. Finally, to validate the results obtained with isolated rabbit atria in the intact heart and in a different species, we performed additional experiments on canine heart in situ.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996) and the rules of the Columbia University Institutional Animal Care and Use Committee.
2.1. Experiments with isolated rabbit tissue
2.1.1. Atrial preparations
Young mature male New Zealand White rabbits (90–100 days old, 2–2.5 kg) were anesthetized with sodium pentobarbital (30 mg/kg i.v.) and were heparinized (1000 U/kg). Their hearts were excised and placed in Tyrode's solution equilibrated at 37 °C with 95% O2/5% CO2 and containing (mmol/l): NaCl 131, NaHCO3 18, KCl 4, CaCl2 0.9, MgCl2 0.5, NaH2PO4 1.8 and dextrose 5.5. Right and left atria were isolated, opened to expose endocardial surface, pinned to the bottom of a 4-ml tissue bath (Fig. 1A), and superfused with Tyrode's solution (T = 37 °C, pH 7.35 ± 0.05) at 12 ml/min. The bath was connected to ground via a 3 M KCl/Ag/AgCl junction. Two bipolar Teflon-coated silver stimulating electrodes were attached to each preparation: near the sinus node (SN) and within the CS ostium in the right atrium and near Bachmann's bundle (BB) and within the ostia of right and left inferior pulmonary veins (PV) in the left atrium (Fig. 1A).
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2.1.2. Electrophysiologic studies
All preparations were impaled with 3 mol/l KCl-filled glass capillary microelectrodes having tip resistances of 10–20 M
. Transmembrane APs were recorded from SN and CS regions in the right atrium and BB and PV regions in the left atrium (Fig. 1A). Recording sites were located 3–4 mm from stimulating electrodes. The maximum upstroke velocity of the AP (Vmax) was obtained by electronic differentiation with an operational amplifier. The electrodes were coupled by an Ag/AgCl junction to an amplifier with high input impedance and input capacity neutralization. Transmembrane action potentials and Vmax signals were digitized with an analog-to-digital converter (DaqBoard 2000, Iotech) and stored to PC for subsequent analysis. For stimulation of preparations, standard techniques were used to deliver square-wave pulses 1.0 ms in duration and 1.5 times threshold through bipolar PTFE-coated silver electrodes. Experimental protocols were started after 1 h of superfusion in control Tyrode's solution while pacing from SN region (right atrium) or BB region (left atrium) at a cycle length (CL) of 400 ms. At that time preparations had fully recovered and displayed stable electrophysiological characteristics.
2.1.3. Protocols
2.1.3.1. Burst pacing protocol
An intermittent burst pacing protocol was developed to mimic an intermittently bursting focus in sleeves of CS or PV. For each 5-min period preparations were driven for 4.5 min from SN or BB regions at CL=400 ms (S1) followed by 30 s of stimulation from CS or PV at CL=200 ms (S2) (Fig. 1B). This pattern of pacing was applied for 3 h and its effect was evaluated at the end of each hour. All records were made at the end of 4.5 min of pacing at CL=400 ms (steady-state). We considered the SN and BB sites as representing those from which impulses normally propagate to activate the right and left atria, respectively (although for left atrium, use of BB this way is an oversimplification). The CS and PV sites were considered to represent those in vasculature from which ectopic impulses might arise.
2.1.3.2. Pharmacological interventions
The effects of the following compounds on burst pacing protocol-induced changes in atrial repolarization were examined: the β-adrenergic receptor blocker, propranolol, 0.2 µM; the muscarinic receptor blocker, atropine, 1 µM; the dihydropyridine receptor blocker, nifedipine, 1 µM; the modulator of SR Ca2+-release channels, ryanodine, 0.03 µM; the Ca2+-sensitive K+ channel blocker, apamin, 0.1 µM (all from Sigma, USA) and the AT-1 receptor blocker, losartan, 2 µM (Merck, Germany). Drugs were administered after the period of adaptation and were present throughout each experiment.
2.1.3.3. Bigeminal pacing
We intervened with bigeminal pacing to probe atrial vulnerability to arrhythmias (Fig. 1C). The protocol was derived from one used clinically by Attuel et al. to unmask paroxysmal atrial fibrillation in human subjects [13]. Preparations were paced for 3 min from SN or BB regions at CL=250 ms (S1). Then every second S1 was substituted with the stimulus S2 delivered from CS or PV and the S1–S2 interval was gradually decreased until the effective refractory period was reached (not every S2 induced a propagated response). S1–S2 was then increased by 3–4 ms to attain a stable capture during bigeminal pacing. This continuous sequence of the long–short cycles was applied during a 5-min period.
2.2. Validation of the experimental model in canine hearts in situ
It was important to test whether the phenomena observed in the isolated atria were consistent with those occurring in the intact heart. Hence, 6 female mongrel dogs (23–25 kg, 2–4 years old) were anesthetized with thiopental sodium, 17 mg/kg, intubated and ventilated with 1.5–2.0% isoflurane and oxygen (2 L/min). Standard limb lead electrodes were attached and the dogs were monitored with continuous ECG recordings. The dogs were placed with their left side down on an operating table fitted with a heating pad to maintain body temperature within physiological range. A right thoracotomy was performed and the heart was exposed in a pericardial cradle. A bipolar pacing electrode was sewn onto the mid-right atrium (MRA) for delivery of pacing impulses. Subsequently, the coronary sinus was identified and cannulated with a decapolar 5F (St Jude Medical) catheter for coronary sinus monophasic action potential recordings and for delivery of burst pacing. Similarly a quadripolar 5F (St Jude Medical) catheter was placed into the MRA region via the inferior vena cava. All dogs were paced from the MRA for 1 h at a CL 10% less than the intrinsic sinus CL prior to obtaining control recordings (pacing CL=473 ± 24 ms). For the next hour the burst pacing protocol was applied as follows: for each 5-min period dogs were paced for 4.5 min from MRA followed by 30 s of stimulation from the CS at CL=300 ms. The dogs were then allowed to recover for 15 min paced only from the MRA. Records were made during MRA pacing in control, post burst pacing and after 15 min of recovery. In four additional dogs, nifedepine was administered intravenously as an initial bolus of 30 µg/kg followed by a continuous infusion of 3 µg/kg/min starting at the time when pacing from the MRA was initiated and continued through the recovery period. The remainder of the protocol was as above. Fig. 2 shows the effect of 1 h burst pacing on the relative changes of MAP duration in two sites in the canine right atrium. Control values were 195 ± 6 ms for MRA and 191 ± 8 for CS. Similar to the results with rabbit right atrium (see Results), burst pacing induced MAP shortening at the vascular site but not in the site of dominant pacing. Also consistent with rabbit atrium, (see Results) in the presence of nifedipine, burst pacing failed to alter repolarization at either site.
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2.3. Data analysis
Conduction time (CT) to either site was defined as the time between S1 and the phase 0 upstroke of the corresponding AP. Repolarization time (RT90) was measured from S1 to 90% of AP repolarization (APD90) and was equal to CT+APD90. Data are expressed as mean ± S.E.M. The statistical techniques were one-way or two-way analysis of variance for repeated or non-repeated measures. Bonferroni's test was used when the F value permitted. Significance of incidence of arrhythmias was evaluated with Fisher's exact test. Significance was determined at P<0.05.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.1. Burst pacing and atrial repolarization in rabbit atrium
Representative records from one right and one left rabbit atrium during application of the burst pacing protocol are shown in Fig. 3A. There was little change of repolarization in the sites of dominant pacing in both atria (SN and BB). However, the sites nearer the burst pacing electrode (CS and PV) showed progressive shortening of AP duration altering the repolarization gradient between these locations and their respective reference locations (SN and BB). Although the net effect of pacing at the vascular sites resulted in shortening of local action potential durations, the difference in control repolarization times between the two locations was such that the gradient for repolarization actually increased with pacing in the right atrium but decreased in the left atrium, as summarized in Fig. 3B. Because conduction time remained unchanged over the 3-h protocol (Fig. 3B), alterations in repolarization gradient resulted only from AP duration shortening in CS and PV regions.
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To determine whether the influence of burst pacing is site-specific, we applied the entire protocol of dominant pacing at CL=400 ms and 30 s bursts at CL=200 ms through the electrodes located at SN or BB. Representative records and summary data for right atria are shown in Fig. 4A and B. There were no changes in time course of repolarization in both SN and CS recording sites over the 3-h protocol. In yet other control experiments we paced the right atrium continuously for 3 h at CL=400 ms from the SN region (Fig. 4C and D). Here, too, no change in repolarization and in gradient between SN and CS was seen. Identical experiments to those in Fig. 4A–D were performed in left atrial preparations and the same results–no change in repolarization–were obtained (data not shown). These data also indicate that our preparations were stable over the time of the experiment.
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The total duration of rapid pacing from the ectopic site during the 3-h burst pacing protocol was 18 min. This raises the question of whether the delivery of ectopic pacing in intermittent bursts over 3 h is important to the changes in repolarization observed, or–alternatively–if the total duration of rapid pacing determines the results seen. Therefore, an additional series of control experiments was performed on right atria. After adaptation and obtaining control records while pacing from SN at CL=400 ms, we continuously paced preparations for 18 min from CS at CL=200 ms. Pacing site was then switched to SN again (CL=400 ms) and records were made for 4–4.5 min. No changes in RT90 were observed in either region: in control, 108 ± 6 ms in SN and 103 ± 7 ms in CS; after rapid pacing, 106 ± 6 ms and 101 ± 8 ms, respectively (n = 6, P>0.05 for both regions).
3.2. Pharmacological testing in rabbit atrium
Fig. 5 shows the time course of repolarization in rabbit left and right atria during application of burst pacing protocol in the presence of propranolol, nifedipine, ryanodine and apamin. Propranolol (2 h superfusion prior to onset of pacing) had no effect on AP duration and did not prevent pacing-induced APD shortening in CS (A) and PV (B). One hour superfusion with nifedipine led to a significant shortening of APD90 in all regions of right (C) and left (D) atria. Subsequently, no changes in APD90 were seen at all recording sites over the 3-h burst pacing protocol. Ryanodine (2 h superfusion) induced significant APD90 lengthening in all regions (E and F). In the presence of ryanodine, APD90 then remained unchanged over the 3-h burst pacing protocol. Superfusion with apamin for 30 min had no effects on APD90 at SN and BB and significantly prolonged APD90 in the regions close to the CS and PV (G and H). In the presence of apamin, no changes in APD90 were observed at all recording sites over the 3-h pacing protocol.
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The effects of the AT-1 receptor blocker, losartan and muscarinic blocker, atropine on burst pacing-induced alterations in repolarization were studied as well. As with propranolol (Fig. 5A and B) neither of these compounds modified the burst pacing-induced APD90 shortening in the CS or PV regions (data not shown).
3.3. Burst pacing and vulnerability of rabbit atria to arrhythmias
Bigeminal pacing at the shortest S1–S2 interval that propagated was used to test vulnerability of rabbit atria to arrhythmias. Fig. 6(A–D) provides an example of bigeminal pacing applied to the right atrium in control. After the minimum S1–S2 was identified, the atrium was bigeminally paced for 5 min, and no arrhythmias were seen (D). The same bigeminal pacing protocol was applied after 3 h of burst pacing (E–H). Here during bigeminal pacing, premature depolarizations were observed (H). Note the shorter minimum S1–S2 interval after the burst pacing protocol that resulted from a shortening of repolarization at the coronary sinus (CS) site.
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Fig. 7 shows summary data for bigeminal pacing. In right atria (A), there were no arrhythmias during bigeminal pacing in control whereas 3 h of burst pacing (3 h BPP) led to a significant increase of the incidence of arrhythmias (premature depolarizations). In contrast, continuous pacing at CL=400 ms for 3 h from SN region alone (3 h SNP) did not elicit bigeminy-induced arrhythmias (A). Burst pacing protocol resulted in a significant shortening of the minimum S1–S2 interval whereas continuous pacing from SN region did not alter S1–S2 (B). In contrast to right atria, bigeminal pacing failed to induce arrhythmias in left atria either before or after 3 h of burst pacing (C) whereas burst pacing led to a similar shortening of the minimum S1–S2 interval (D). Continuous pacing at CL=400 ms for 3 h from BB region alone (3 h BBP) did not predispose to bigeminy-induced arrhythmias (C) and did not alter S1–S2 (D).
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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We have used pacing in a specific, patterned fashion at sites that activate the myocardium via pathways different from that of sinus rhythm, representing a rare event. Our experiments demonstrate that rarely occurring bursts of rapid activity applied to coronary sinus or pulmonary vein for 3 h gradually change repolarization in the region of rapid pacing (PV or CS), but not distally, thereby altering the dispersion of repolarization. Importantly, the effect of burst pacing to change the atrial repolarization gradient is site sensitive: if both dominant pacing and bursts of rapid pacing are delivered through the electrodes located at dominant sites (sinus node of Bachmann's bundle) the atrial repolarization pattern remains unaltered. This phenomenon is consistent with studies of intact canine heart in which 2 h of pacing from the left atrial appendage at a rate higher than sinus alters activation and modifies atrial repolarization whereas right atrial pacing at the same rate does not affect the atrial repolarization gradient [11]. It was critical in the present study to deliver burst pacing to a region outside the site of normal atrial impulse origin (SN region) or outside a site of normal entry of impulses from right to left atrium (Bachmann's bundle). Only in this way was alteration of atrial repolarization noted. It was also critical to deliver rapid pacing as intermittent bursts: continuous rapid pacing from ectopic sites during a time interval equal to the total time of burst pacing did not alter atrial repolarization.
Because electrical stimulation can induce neurotransmitter release from nerve terminals we tested whether our results might derive from neurohumoral actions in the coronary sinus and pulmonary vein regions. That both atropine and propranolol failed to alter the decrease in repolarization induced by pacing argues strongly against any neurohumoral action here. Moreover, the losartan experiments argue against any role for angiotensin II.
That apamin prevented the atrial repolarization changes suggests that burst pacing induced shortening of APD in CS and PV regions might result from altered function of Ca2+-activated K+ current (IK,Ca). Apamin-sensitive small-conductance Ca2+-activated K+ (SK) channels have been found in rabbit [14] as well as human myocytes [15]. The channel is expressed differentially with more abundant SK channel in the atria compared with the ventricles [14,15]. IK,Ca is activated by calcium transients [14–16] and its block by apamin significantly prolongs AP duration [15,17].
The contribution of IK,Ca to the changes in repolarization observed in the present study is supported by the following results: Burst pacing-induced shortening of APD was prevented by: (i) the SK channel selective blocker apamin [18], (ii) nifedipine which inhibits ICa,L [19] and decreases the calcium transient, (iii) ryanodine which, at the concentration used, activates release of Ca2+ from and thereby depletes intracellular stores [20] and decreases the calcium transient. Importantly, superfusion with apamin before application of the burst pacing protocol prolonged APD in CS and PV but not in SN and BB regions (Fig. 5G and H), suggesting more abundant SK channels in the venous regions.
The bigeminal pacing experiments were performed to test whether intermittent burst pacing might affect atrial vulnerability. Increased heterogeneity of repolarization is an important factor in experimental models of AF [21,22] and is associated with paroxysmal AF in adult and old human hearts [23,24]. Our data from the right atrium are consistent with these observations. In control, right atrial repolarization was homogeneous and bigeminal pacing did not induce arrhythmias. The 3-h burst pacing protocol created a repolarization gradient and resulted in a high incidence of arrhythmias in response to bigeminal pacing.
These findings in right atrial preparations provide a vehicle for exploring the initiation of ectopic rhythms as a rare event (rapid firing within the CS) conditions an adjacent substrate at the CS orifice over a brief period of time. In contrast to studies of long-term pacing in animals, very little is known of the remodeling induced by ectopic foci that fire rarely. Attuel et al. [13] noted that bigeminal pacing from an ectopic atrial site in human subjects induced a significantly greater incidence of paroxysmal AF in those patients who previously had experienced paroxysms of AF than in a population of controls. The bigeminal pacing protocol we employ is modeled after this. Attuel et al's observation is important because the pacing intervention was "minimally invasive" (imposing bigeminal patterns only) and because it elicited the expression of a rare event in those patients. However, no mention was made of the mechanism or type of remodeling that occurred to allow such pacing protocols to initiate AF. In another study of patients with paroxysmal AF, brief intervals of rapid pacing shortened ERP and induced bursts of AF [25].
A key factor in the remodeling in the sinus node/coronary sinus preparation may be the increased dispersion of repolarization that evolves between these sites. This provides an important contrast with the PV/BB preparations in which, despite a prominent repolarization gradient between the two left atrial sites in control, no arrhythmias were seen with bigeminal pacing. Moreover, the remodeling in the PV region actually reduced the dispersion of repolarization in the left atrial preparations. We suggest the following explanation for the different incidences of arrhythmic activity in the right and left atrial preparations. In addition to heterogeneity of repolarization, the magnitude of the minimum S1–S2 interval is an arrhythmogenic factor. That is, the earlier a premature stimulus is applied the higher the likelihood of arrhythmias. In the right atrium, both arrhythmogenic factors are absent in control (there are homogeneous repolarization and a long minimum S1–S2) and present after the burst pacing protocol (a prominent repolarization gradient and shortened minimum S1–S2). In contrast, in the left atrium, only one factor is present either in control (prominent repolarization gradient but long minimum S1–S2) or after the burst pacing protocol (shortened minimum S1–S2 but significantly decreased heterogeneity of repolarization).
The failure of intermittent burst pacing to increase vulnerability to arrhythmias in the left atrial preparations contradicts the clinical observation that spontaneous ectopic beats originating in the PV can initiate atrial fibrillation [4,5]. It may be that a shortcoming of the model we have used is that the isolated left atria preparation itself, while permitting remodeling of repolarization to occur, is inimical to the occurrence of arrhythmias. In contrast, the right atrial preparation does facilitate arrhythmogenesis which at the very least is consistent with arrhythmic activity arising from the CS clinically, and which may or may not be extrapolated to arrhythmias arising in PV as well.
The data from canine hearts in situ are important because they demonstrate that the effects of rapid burst pacing on atrial repolarization gradient are not limited to the isolated rabbit atrium. In agreement with findings in rabbit atria, we observed a shortening of repolarization at the site of burst pacing (CS) but not distally (MRA). Furthermore, in canine atrium, the effect of rapid burst pacing was also blocked by nifedipine.
In conclusion, atrium is sensitive to rare activation from foci outside the regions of dominant activation (SN region) or direct impulse entry (BB). Rare bursts of rapid activity mimicking an intermittently bursting focus in CS or PV change repolarization in the region of pacing, but not distally, thereby altering dispersion of repolarization. Modulation of Ca2+-sensitive K+ channels may contribute to the changes of repolarization in CS and PV regions. Alterations of atrial repolarization gradient and shortening of coupling interval for premature beat induced by rare bursts of rapid activity creates an arrhythmogenic substrate and can be considered as an early step in atrial electrophysiologic remodeling.
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Acknowledgements |
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The authors express their gratitude to Ms. Nimee Bhat for her assistance in performing the studies and to Ms. Laureen Pagan for her careful attention to the preparation of the manuscript. The study was supported by NHLBI grants HL 67101 and Hl 67449.
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Notes |
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Time for primary review 15 days
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