HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 287/1/H178    most recent 00085.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Miyauchi, Y. Articles by Karagueuzian, H. S. Search for Related Content PubMed PubMed Citation Articles by Miyauchi, Y. Articles by Karagueuzian, H. S.

Electrical current-induced atrial and pulmonary vein action potential duration shortening and repetitive activity

Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, and ¹David Geffen School of Medicine, University of California-Los Angeles (UCLA), and ²Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, California 90048

Submitted 29 January 2004 ; accepted in final form 27 February 2004

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
The influence of threshold electrical currents (EC) during regular drive on pulmonary vein (PV) and atrial myocardial cell action potential (AP) duration (APD) is unknown. We determined the effects of EC on cellular APD of PV, atria, and ventricles in isolated perfused and superfused male rat hearts (Fisher-344 strain, 3–4 mo old) at 37°C (n = 14). We determined APD changes caused by subthreshold and threshold EC synchronized with a distant pacing electrode and delivered nearby cells from which transmembrane APs were recorded with a glass microelectrode. Progressive APD shortening (P < 0.001) and membrane hyperpolarization (P < 0.05) developed over a 20-s interval in the PV and atrial cells when the EC was delivered at <2 mm but not at >4 mm from the microelectrode. No such effects were seen in ventricular muscle cells. APD fully recovered 25 s after the cessation of EC application. Premature stimuli applied during EC-induced shortening of the APD caused rapid repetitive PV and atrial activity lasting two to five beats. Atropine (2 µM, n = 10) prevented, whereas propranolol (2 µM, n = 5) had no effect, on EC-induced APD shortening or repetitive activity. We conclude that EC shortens the APD and hyperpolarizes the membrane by local release of acetylcholine and causes the steep repolarization gradient in the vicinity of the current source leading to repetitive activity in atrial and PV cells during premature stimulation.

acetylcholine; reentry; dispersion of repolarization; arrhythmias

Recently, the PVs have become increasingly implicated in the genesis of atrial fibrillation and, as a result, are subject to growing electrophysiological, pacing, and mapping studies (4, 5, 9, 10, 12). We therefore sought to determine the influence of ECs on PV myocardial cell APD and compared it in atrial and ventricular myocardial cells. Specifically, we hypothesized that near-threshold EC applied at rates just above the intrinsic sinus rate, shortens the APD of PV and atrial myocardial cells, and hyperpolarizes their resting potential while exerting no influence on ventricular myocardial cell APs because of scarce parasympathetic innervation of the ventricles (7, 13, 24, 28, 30). In the present study, we used rats to test our hypotheses because the adventitia of the rats' PV, unlike those of canine and swine PVs, contain only a thin layer of collagenous material allowing glass microelectrode impalement and recording from intact PV-atrial tissues with relative ease.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Tissue Preparations

This study protocol was approved by the Institutional Animal Care and Use Committee and followed the guidelines of the American Heart Association. Male rats of the Fisher-344 strain (3–4 mo old) were anesthetized with ketamine (100 mg/kg) and xylazine (10 mg/kg) injected intraperitoneally. The hearts and lungs were quickly removed, and the aorta was cannulated (11). The isolated heart-lung preparations were placed in a tissue bath, and the aorta was perfused with Tyrode solution at a rate of 8 ml/min and at 37°C. The preparations were fixed to the tissue bath with the dorsal face of the heart facing up. The ventricles and lungs were held in place secured using fine stainless steel pins. With this arrangement, the PVs as well as the right (RA) and left atria (LA) became well exposed, thereby allowing glass microelectrode implement (Fig. 1). The composition of the solution was as follows (in mmol/l): 125.0 NaCl, 4.5 KCl, 0.5 MgCl₂, 1.3 CaCl₂, 1.2 NaH₂PO₄, 24 NaHCO₃, and 5.5 glucose. The solution was gassed with a mixture of 95% O₂-5% CO₂ with a resultant pH of 7.4. The isolated tissues were also superfused with Tyrode solution at 37°C at a rate of 15 ml/min. The hearts were immobilized using cytochalasin D (5 µM) to allow stable and continuous microelectrode recordings (11).

View larger version (18K): [in this window] [in a new window]   Fig. 1. Schematic presentation of the anatomic localization of the isolated tissues (A), locations of the pacing and current electrode relative to the glass recording microelectrode (B), and the pacing and electrical current (EC) application protocol (C). Action potentials (APs) were sequentially recorded from the left lower lobe of pulmonary venous (PV) trunk, the right atrial (RA) free wall near the junction with the inferior vena cava, and the base of the left atrial (LA) appendage. The recording sites are indicated by the hatched areas in the schematic drawing of the isolated preparation (A). The pacing electrode was located at distances >10 mm (usually in a different heart chamber) continuously drive the atria (pacing artifact). Current pulses of different strengths (0.1, 1, and 10 mA) and at increasing distances from the microelectrode were then applied for 30 s (current artifact) while regular pacing by the pacing electrode continued uninterrupted.

Regular pacing was achieved using bipolar electrodes, which were constructed from two Teflon-coated silver wires (0.2 mm in diameter) with only the tips of the wires exposed. Rectangular twice threshold current pulses of 2-ms duration were delivered by a constant-current source (model A385, World Precision Instruments). Transmembrane APs were recorded with a standard glass microelectrode filled with 3 mol/l KCl (22). APs were sequentially recorded from the left lower lobe of the pulmonary venous trunk located 5–7 mm away from the junction of the LA, the RA free wall near the junction with the inferior vena cava, the base of the LA appendage, and the left ventricular (LV) apex. The pacing electrode was placed >10 mm away, usually in a different chamber, from the recording glass microelectrode (Fig. 1). The hearts were continuously paced at a cycle length (CL) slightly shorter (<10%) than the sinus CL using current strengths just above the diastolic current threshold. A second similarly constructed bipolar electrode (the "current electrode"), synchronized with the pacing electrode, was placed at <1 mm and at progressively longer distances, up to 10 mm, away from the recording microelectrode (Fig. 1).

The current electrode was synchronized with the pacing electrode to deliver current pulses of 2-ms duration at increasing strengths starting from 0.1, 1, and then to 10 mA. With this recording arrangement, we could test the influence of both the strength and distances of the current source on PV, RA, LA, and LV myocardial cell actions and resting membrane potentials. The influence of the synchronous current pulses applied at increasing strengths and at increasing distances from the recording microelectrode was continuously recorded for a 30-s interval of pacing. Continuous recordings were also made for 30 s before and 30 s after the cessation of the current application while the isolated hearts were continuously paced at the same pacing rate as during the application of synchronous EC. All electrical signals were digitized at 3 kHz with 12-bit accuracy (Axon Instruments) (22). APD at 90% repolarization (APD₉₀) and maximum diastolic potential (MDP) were measured using custom-written software. The APD₉₀ of all beats during a 30-s period before, 30 s during, and 30 s after the cessation of EC application of increasing intensities and at increasing distances from the recording microelectrode were measured and compared with each other. The repolarization gradient (in ms/mm) was computed by dividing the difference in the APD over a 4-mm distance from the EC source (19, 20). The effective refractory period (ERP) was measured by the extrastimulus methods during regular pacing at a CL of 400 ms. Both S1 (regular pacing stimulus) and S2 (premature test stimulus) were applied at the same site using a bipolar electrode with a twice diastolic threshold current strength of 3-ms duration.

Autonomic Blockade

We tested the influence of muscarinic cholinergic blockade with atropine (2 µM) and -adrenergic receptor blockade with propranolol(2 µM) on five isolated heart preparation on EC-induced changes on atrial and ventricular myocardial cell APD and MDP. We also tested the effect of total autonomic blockade by combining atropine (2 µM) with propranolol (2 µM) in these five preparations (16).

Histological Analysis

Five-micrometer-thick longitudinal sections at the PV-LA junction and two to three sections from both atria were stained with Masson-trichrome to identify collagen, muscle, and nerves in the PV and atria. Immunoperoxidase staining for myoglobin was used to distinguish striated (cardiac) muscle from smooth muscle cells (21).

Statistical Analysis

Comparisons of the influence of EC on the APD₉₀ and MDP applied at increasing strengths (0.1, 1, and 10 mA) and at increasing distances (from 1 to 10 mm) from the recording glass microelectrode were performed using ANOVA with Bonferroni's correction for multiple comparisons. P < 0.05 was considered significant.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Time Course of EC on Cardiac APs

Figure 2 illustrates the time course of APD shortening during EC application synchronized with regular pacing in a representative PV myocardial cell recording located <1 mm from the EC source. Pacing from the RA at a rate just above the intrinsic sinus rate (200-ms CL) had no effect on the PV cell APD. However, when synchronous EC at a strength of 1 mA was applied at <1 mm from the PV cell, the APD of the PV cell underwent a progressive shortening that reached a plateau within 15 s (Fig. 2, A and B). After the cessation of the synchronous EC application, while pacing of the heart regularly from the RA at a CL of 200 ms continued, the PV cell fully recovered its APD to its pre-EC, pacing APD within 25 s (Fig. 2, A and B). There were no significant differences in the time course of APD shortening between PV and atrial cells (range: 7–22 s, mean 15 ± 7 s). The greatest APD shortening in response to applied EC developed when the EC source was <1 mm from recording microelectrode. Consequently, in all subsequent studies, all the measurements and statistical analyses of the influence of EC and drug effects on cardiac cell APD, ERP, and MDP were made on recordings obtained 30 s after the start of the synchronous EC application at distances <1 mm from the recording microelectrode.

View larger version (22K): [in this window] [in a new window]   Fig. 2. Time course of AP duration (APD) at 90% repolarization (APD90) shortening and recovery after the onset and offset of EC application in the PV. Note that APD does not change during pacing from the LA at a cycle length of 5% shorter than the spontaneous sinus cycle length (A, Sinus and Pacing). B: all 150 consecutive beats during the entire 30-s current application at a cycle length of 200 ms (Pacing + Electric Current). Progressive ADP90 shortening, reaching a plateau within 20 s, is evident. Full recovery of ADP90 and loss of membrane hyperpolarization develops within 20 s of synchronous current offset (A and B).

Effects of EC strength. We found that both the strength and distance of the EC source from the recording microelectrode exerted strong influence on the PV and atrial cell APD and membrane potential. Figure 3 illustrates the influence of increasing EC strength at a fixed distance (<1 mm) on the APD in a representative PV myocardial cell. A significant strength-dependent APD shortening also developed in the RA and LA myocardial cells (Figs. 4 and 5). At a given site, increasing the current strength from 0.1 to 1 mA significantly increased the magnitude of the APD shortening. Increasing the current strength from 1 to 10 mA, however, did not further shorten the APD beyond the shortening induced by 1 mA (Figs. 4 and 5 and Table 1). The EC had no effect on ventricular myocardial cell APD regardless of its strength (Figs. 4 and 5 and Table 1). Table 1 summarizes the APD data in all atrial, PV, and LV myocardial cells obtained at a distance <1 mm from the EC source.

View larger version (24K): [in this window] [in a new window]   Fig. 3. Effects of subthreshold (A) and suprathreshold (B) currents on PV myocardial cell AP. The LA (>10 mm from the microelectrode) was continuously paced at a cycle length of 200 ms. A: synchronous application of 0.1-mA current within 1 mm from the microelectrode (downward arrows and dashed lines) reduced the APD90 from 67 to 50 ms 30 s later. B: an increase in the amplitude of the synchronous current to 1 mA resulted in APD90 shortening to 33 ms 30 s later. PV-Beg and LA-Beg, PV and LA bipolar electrograms, respectively; PV-Stim, stimulus artifact caused by the current application. Note that 1 mA, unlike 0.1 mA, resulted in capture of PV myocardial cells. Numbers below each AP represent APD90.

View larger version (21K): [in this window] [in a new window]   Fig. 4. Superimposed APs recorded 1 mm away from the current source in the RA, PV, LA, and left ventricle (LV) immediately before (Pre) and at the end of 30 s of current delivery (Post) of 0.1, 1.0, and 10 mA. The currents were synchronized with the distant pacing electrode at a cycle length of 200 ms. Arrows indicate 90% repolarization. Note that PV, RA, and LA myocardial cells show APD shortening after the onset of synchronous current delivery, whereas no APD shortening developed in the LV myocardial cell.

View larger version (26K): [in this window] [in a new window]   Fig. 5. Histograms of RA, LA, PV, and LV myocardial cell APD90 after 30 s of current application (cycle length of 200 ms) using increasing strengths (0.1, 1.0, and 10 mA). The current electrode was located at <1 mm from the cells (recording microelectrode).

View larger version (19K): [in this window] [in a new window]   Fig. 6. Representative superimposed RA APs immediately before (Pre) and 30 s after application of ECs (Post) of 0.1 mA (A), 1 mA (B), and 10 mA (C). The APs were recorded at progressively longer distances (>1–10 mm) from the current source. Downward arrows indicate APD90 before ECs, and upward arrows indicate APD90 at the end of 30 s EC application. Note that the influence of ECs greatly diminishes at all distances >2 mm at all three current strengths.

View larger version (11K): [in this window] [in a new window]   Fig. 7. Plot of the effects of current strengths and distances from the current source of RA cell APD90. Significant APD shortening effect of the ECs is apparent only at distances <2 mm.

Increasing the EC from 0.1 to 1 mA caused a significant increase (P < 0.05) of the MDP in PV and atrial cells. Increasing the current strength from 1 to 10 mA did not increase the MDP (hyperpolarization) beyond that observed with 1 mA. Figure 8 illustrates an example in PV myocardial cell. EC had no effect on ventricular myocardial cell MDP at all current strength and all distances. Table 2 summarizes the results of EC of increasing strengths on the MDP of all four cells recorded from a distance <1 mm from the EC source.

View larger version (23K): [in this window] [in a new window]   Fig. 8. Influence of EC on APD and maximum diastolic potential in a PV. The EC of 1 mA was applied at <1 mm away from the PV cell during regular LA pacing. Hyperpolarization of 3.6 mV is apparent in the enlarged recordings at the bottom.

Bipolar excitability threshold (minimum current strength that evokes a propagated response) was not significantly different at all four recording sites (Table 3). Atropine and propranolol either singly or in combination had no effect on excitability on all four cell types (Table 3). In all tissues, a current strength of 0.1 mA was subthreshold and failed to capture the atria or ventricle. Atropine (2 µM) blocked EC-induced APD shortening and membrane hyperpolarization in PV and atrial cells but had no detectable effect on ventricular myocardial cells (Fig. 9 and Tables 1 and 2). In contrast, however, 2 µM propranolol (n = 5) had no influence on EC-induced membrane hyperpolarization or APD shortening in the PV, RA, and LA (Tables 1 and 2). Similarly, propranolol had no effect on ventricular MDP and APD (Tables 1 and 2). Figure 9 shows representative RA cell shortening of the APD and membrane hyperpolarization in response to EC in the presence of propranolol. The combination of atropine and propranolol (complete autonomic blockade) did not cause any significant change in APD compared with atropine alone (Table 1).

View larger version (31K): [in this window] [in a new window]   Fig. 9. Effects of 2 µM propranolol (A) and 2 µM atropine (B) before and after the onset of 1-mA current delivery within 1 mm of the RA. In both A and B, *1 denotes the paced beat before the onset of current delivery and *2 denotes the end of 30 s of 1-mA current delivery synchronized with the distant pacing electrode in the LA. Note that propranolol did not prevent 1-mA current-induced APD shortening (superimposed recordings in A), whereas atropine completely abolished current-induced APD shortening (superimposed recordings in B).

EC-induced shortening of the APD was associated with a significant (P < 0.01) shortening of the ERP in PV and atrial cells. The ERP of atrial and PV cells (n = 5) decreased by a mean of 16 ± 7 ms when the intensity of the regular drive (S1S1) was 0.5 mA. Raising the S1S1 drive current intensity to 1 mA (S2 stimulus intensity fixed at 1 mA) caused a significant (P < 0.05) further shortening of the ERP by a mean of 33 ± 9 ms. However, when the S1S1 current strength was raised to 10 mA, no further ERP shortening could be detected (30 ± 9 ms, NS compared with 1 mA). EC-induced shortening of the ERP allowed the S2 stimulus to elicit APs from significantly shorter coupling intervals (Fig. 10). These short-coupled APs elicited rapid repetitive PV and atrial activity at CLs of 60–90 ms (Fig. 10). The rapid activity could be induced in all five tissues tested and could last only for three to seven beats (Fig. 10).

View larger version (24K): [in this window] [in a new window]   Fig. 10. Induction of repetitive RA responses by premature stimulation during an increase in the intensity of regular pacing drive (S1S1) train from 0.5 to 10 mA while maintaining the S2 stimulus intensity fixed at 1 mA. S1S1 and S2 were applied at the same site and the AP recording microelectrode was within 1 mm of the pacing electrode. Note that after an increase in the regular pacing drive current intensity the earliest captured premature coupling interval decreased from 41 to 25 ms, reflecting a decrease in the effective refractory period. The shorter S1S2 resulted in rapid repetitive atrial activity. Still, shorter premature stimuli (i.e., 40 ms during S1S1 of 0.5 mA and 24 ms during S1S1 of 10 mA) resulted in block (arrows in the right panels).

Figure 11 shows a longitudinal section of a Masson trichrome-stained LA-PV junction in a representative rat. Five to eight cell layers of myocardial cells are clearly visible in the PV that penetrates deep inside the lung (Fig. 11A). A 5- to 10-µm-thick layer of connective tissue overlays the adventitial site of the PV (Fig. 11C). The presence of striated, myocardial-type myocytes in the PV was confirmed with the positive myoglobin staining (Fig. 11D). Nerve fibers were also identified in the atria and PV (Fig. 11B) (21).

View larger version (78K): [in this window] [in a new window]   Fig. 11. Longitudinal and cross sections of the LA-PV junction in a representative rat. A: Masson trichome-stained tissue showing 5–8 cell layers of myocardial cells in the PV that penetrate deep inside the lung. The three boxed regions are enlarged and shown in greater detail in B–D, respectively. B: a nerve ending at the PV-LA junction. C: a relatively thin 5- to 10-µm-thick connective tissue overlays the adventitial site of the PV. D: the myocardial origin of the cells in the PV was confirmed with their positive myoglobin staining.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION GRANTS REFERENCES

To our knowledge, this is the first demonstration that sub-and suprathreshold ECs shorten PV and atrial myocardial cell APs and increase MDP by a mechanism consistent with local release of ACh. The results of the present study are compatible with previous studies that demonstrated ACh-mediated atrial cell APD shortening with EC and the lack of any change in ventricular myocardial cell APD (1–3, 8). Furthermore, shortening of PV ERP with EC-induced ACh release is consistent with previous studies that showed thoracic vein ERP shortening with vagal stimulation (29). In the present study, we also demonstrated that APD shortening and membrane hyperpolarization, unlike in previous reports, were achieved using relatively low rates of stimulation (i.e., 5% faster than sinus rate) while using sub- and just suprathreshold currents. EC-induced shortening of the APD in cells just adjacent to the current source significantly increases the repolarization gradient leading to rapid PV and atrial repetitive activity during premature stimulation.

Mechanisms of EC-Induced APD Shortening

Several of the findings in the present study strongly indicate that EC-induced shortening of the APD result from local release of ACh, which activates I_KACh in atrial cells (17). The ability of atropine, a competitive muscarinic ACh receptor blocker (16, 25, 26), to completely block APD shortening and membrane hyperpolarization provides strong evidence that the EC-induced APD shortening is ACh mediated.

Previous histochemical studies have shown the presence of abundant cholinergic nerve endings in the atria and PV but not in the ventricles (7). Although sympathetic nerves may also influence PV and atrial cell APD, in the present study we found that propranolol had no effect on cardiac APD. One possible explanation may be that the strength and the frequency of the ECs we used in the present study may not be of sufficient amplitude to cause release of catecholamines. Another possibility is that the amount of cathecolamines released may be too small to affect PV and atrial myocardial cell APD. The atria are more densely innervated by cholinergic than by sympathetic fibers (23). Furthermore, the absence of any effect of the ECs on the APD of ventricular cells suggests much less parasympathetic nerve distribution in the ventricle than in the atrium, save perhaps the presence of acetylcholine esterase-positive fibers (plexus) located at discrete subendocardial ventricular sites (7). It is possible that ventricular endocardial ECs rather than epicardial applications of ECs could have caused APD shortening at discrete endocardial sites (18). An in vivo canine study by Zipes et al. (30) showed that sympathetic stimulation results only in a small or no change in the atrial refractory period, whereas vagal stimulation causes profound shortening of the atrial and PV refractory period (29).

Direct Effects of EC on Cardiac APD

It may be argued that the close proximity of the current electrode to the recording microelectrode might accelerate repolarization (6). Several characteristics of EC-induced APD shortening, however, argue against a direct electrical effect on APD. The relatively slow time course of the development of EC-induced electrophysiological changes and the slower return to the pre-EC state strongly suggest that the observed effects are not compatible with direct electrical effects, which are known to developing over a millisecond range (6). Indeed, the time course of APD shortening is relatively slow, i.e., 20 s (time constant of 7 s). Should the ECs have had direct effect on the APD, acceleration of repolarization should have resulted immediately (within milliseconds) after the onset of current application. This, however, was not the case. Similarly, the recovery of the APD after the cessation of the ECs was also a slow process. Consequently, the kinetics of the onset and offset of EC-induced APD shortening is compatible with transmitter release, uptake, and washout mechanisms rather than a direct current effect. Finally, the lack of ventricular cell APD shortening with increasing currents argues against a direct current effect on cardiac cell APD.

Implications

In the present study, we used pacing rates, current strengths, and pulse width, which are commonly used during routine clinical pacing and electrophysiological studies of the PV and atria. Our results suggest that ERP determination at the pacing site may underestimate true refractoriness by EC-induced shortening of the refractory period. In addition, the EC may also increase the local PV and atrial dispersion of refractoriness leading to repetitive activity during premature stimulation independent of the presence of pathological substrates. The induced repetitive activity during pacing of the PV or atria appears to be incompatible with an automatic mechanism caused either by early or delayed afterdepolarizations (EADs and DADs, respectively), because activation of outward current by EC-induced ACh release inhibits cardiac automaticity (13, 27). We could not detect pacing-induced triggered activity by either EAD or DAD with their characteristic smooth transition from MDP to upstroke of the AP (Fig. 10) (27).

Study Limitations

In the present study, we used cytochalasin D to minimize movement to allow stable and continuous recordings from the cell. While it might be expected that cytochalasin D prolongs atrial APD (15), the ability of EC-induced shortening of the APD and the complete suppression with atropine strongly suggest that the use of cytochalasin D did not affect testing of our hypotheses.

	GRANTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
This study was supported in part by American Heart Association Western States Affiliate Grant-In-Aid 0255937Y, University of California-Tobacco-Related Disease Research Program Grant 11RT-0058, National Heart, Lung, and Blood Institute Specialized Center of Research Grant in Sudden Death p50 HL-52319, the Cedars-Sinai Electro Cardiographic Heartbeat Organization Foundation, the Cardiac Arrhythmia Research Enhancement Support Group, and the Piansky Family Trust (to M. C. Fishbein).

	FOOTNOTES

 

Address for reprint requests and other correspondence: H. S. Karagueuzian, 8700 Beverly Blvd., Davis Research Bldg., Rm. 6066, Los Angeles, CA 90048 (E-mail: karagueuzian{at}cshs.org).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION GRANTS REFERENCES

 

1. Amory DW and West TC. Chronotropic response following direct electrical stimulations of the isolated sinoatrial node: a pharmacologic evaluation. J Pharmacol Exp Ther 137: 14–23, 1962.[Abstract/Free Full Text]
2. Blinks JR. Field stimulation as a means of effecting the graded release of autonomic transmitters in isolated heart muscle. J Pharmacol Exp Ther 151: 221–235, 1966.[Abstract/Free Full Text]
3. Brady AJ, Abbott BC, and Mommaerts WFHM. Inotropic effects of trains of impulses applied during the contraction of cardiac muscle. J Gen Physiol 44: 415–432, 1960.[Abstract/Free Full Text]
4. Chen PS, Wu TJ, Hwang C, Zhou S, Okuyama Y, Hamabe A, Miyauchi Y, Chang CM, Chen LS, Fishbein MC, and Karagueuzian HS. Thoracic veins and the mechanisms of non-paroxysmal atrial fibrillation. Cardiovasc Res 54: 295–301, 2002.[Abstract/Free Full Text]
5. Chen SA, Hsieh MH, Tai CT, Tsai CF, Prakash VS, Yu WC, Hsu TL, Ding YA, and Chang MS. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 100: 1879–1886, 1999.[Abstract/Free Full Text]
6. Cranefield PF and Hoffman BF. Propagated repolarization in heart muscle. J Gen Physiol 41: 633–649, 1958.[Abstract/Free Full Text]
7. Ehinger B, Falck B, Persson H, and Sporrong B. Adrenergic and cholinesterase-containing neurons of the heart. Histochemie 16: 197–205, 1968.[CrossRef][ISI][Medline]
8. Euler DE and Scanlon PJ. Acetylcholine release by a stimulus train lowers atrial fibrillation threshold. Am J Physiol Heart Circ Physiol 253: H863–H868, 1987.[Abstract/Free Full Text]
9. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, and Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 339: 659–666, 1998.[Abstract/Free Full Text]
10. Hamabe A, Okuyama Y, Miyauchi Y, Zhou S, Pak HN, Karagueuzian HS, Fishbein MC, and Chen PS. Correlation between anatomy and electrical activation in canine pulmonary veins. Circulation 107: 1550–1555, 2003.[Abstract/Free Full Text]
11. Hayashi H, Wang C, Miyauchi Y, Omichi C, Pak HN, Zhou S, Ohara T, Mandel WJ, Lin SF, Fishbein MC, Chen PS, and Karagueuzian HS. Aging-related increase to inducible atrial fibrillation in the rat model. J Cardiovasc Electrophysiol 13: 801–808, 2002.[CrossRef][ISI][Medline]
12. Hocini M, Ho SY, Kawara T, Linnenbank AC, Potse M, Shah D, Jais P, Janse MJ, Haissaguerre M, and de Bakker JM. Electrical conduction in canine pulmonary veins: electrophysiological and anatomic correlation. Circulation 105: 2442–2448, 2002.[Abstract/Free Full Text]
13. Hoffman BF and Cranefield PF. Electrophysiology of the Heart. New York: McGraw-Hill, 1960.
14. Hoffman BF and Suckling EE. Cardiac cellular potentials: effect of vagal stimulation and acetylcholine. Am J Physiol 169: 377–383, 1952.[Free Full Text]
15. Jalife J, Morley GE, Tallini NY, and Vaidya D. A fungal metabolite that eliminates motion artifacts. J Cardiovasc Electrophysiol 9: 1358–1362, 1998.[ISI][Medline]
16. Katoh T, Karagueuzian HS, Jordan J, and Mandel WJ. The cellular electrophysiological mechanism of disopyramide's dual actions on rabbit sinus node function. Circulation 66: 1216–1224, 1982.[Abstract/Free Full Text]
17. Kurachi Y, Nakajima T, and Sugimoto T. Acetylcholine activation of K⁺ channels in cell-free membrane of atrial cells. Am J Physiol Heart Circ Physiol 251: H681–H684, 1986.[Abstract/Free Full Text]
18. Langberg JJ, Calkins H, Sousa J, El-Atassi R, and Morady F. Effects of drive train stimulus intensity on ventricular refractoriness in humans. Circulation 84: 181–187, 1991.[Abstract/Free Full Text]
19. Laurita KR, Girouard SD, and Rosenbaum DS. Modulation of ventricular repolarization by a premature stimulus. Role of epicardial dispersion of repolarization kinetics demonstrated by optical mapping of the intact guinea pig heart. Circ Res 79: 493–503, 1996.[Abstract/Free Full Text]
20. Laurita KR and Rosenbaum DS. Interdependence of modulated dispersion and tissue structure in the mechanism of unidirectional block. Circ Res 87: 922–928, 2000.[Abstract/Free Full Text]
21. Miyauchi Y, Zhou S, Okuyama Y, Miyauchi M, Hayashi H, Hamabe A, Fishbein MC, Mandel WJ, Chen LS, Chen PS, and Karagueuzian HS. Altered atrial electrical restitution and heterogeneous sympathetic hyperinnervation in hearts with chronic left ventricular myocardial infarction: implications for atrial fibrillation. Circulation 108: 360–366, 2003.[Abstract/Free Full Text]
22. Ohara T, Qu Z, Lee MH, Ohara K, Omichi C, Mandel WJ, Chen PS, and Karagueuzian HS. Increased vulnerability to inducible atrial fibrillation caused by partial cellular uncoupling with heptanol. Am J Physiol Heart Circ Physiol 283: H1116–H1122, 2002.[Abstract/Free Full Text]
23. Pappano AJ. Propranolol-insensitive effects of epinephrine on action potential repolarization in electrically driven atria of the guinea pig. J Pharmacol Exp Ther 177: 85–95, 1971.[Abstract/Free Full Text]
24. Randall WC and Ardell JL. Selective parasympathectomy of automatic and conductile tissues of the canine heart. Am J Physiol Heart Circ Physiol 248: H61–H68, 1985.[Abstract/Free Full Text]
25. Rashba EJ, Cooklin M, MacMurdy K, Kavesh N, Kirk M, Sarang S, Peters RW, Shorofsky SR, and Gold MR. Effects of selective autonomic blockade on T-wave alternans in humans. Circulation 105: 837–842, 2002.[Abstract/Free Full Text]
26. Schauerte P, Scherlag BJ, Patterson E, Scherlag MA, Matsudaria K, Nakagawa H, Lazzara R, and Jackman WM. Focal atrial fibrillation: experimental evidence for a pathophysiologic role of the autonomic nervous system. J Cardiovasc Electrophysiol 12: 592–599, 2001.[CrossRef][ISI][Medline]
27. Wit AL and Cranefield PF. Triggered and automatic activity in the canine coronary sinus. Circ Res 41: 434–445, 1977.[Medline]
28. Zipes DP. Autonomic innervation of the heart: role in arrhythmia development during ischemia and in the long QT syndrome. In: The Heart and Cardiovascular System, edited by Fozzard HA. New York: Raven, 1992, p. 2095–2112.
29. Zipes DP and Knope RF. Electrical properties of the thoracic veins. Am J Cardiol 29: 372–376, 1972.[CrossRef][ISI][Medline]
30. Zipes DP, Mihalick MJ, and Robbins GT. Effects of selective vagal and stellate ganglion stimulation of atrial refractoriness. Cardiovasc Res 8: 647–655, 1974.[ISI][Medline]

This article has been cited by other articles:

				P. Comtois, M. Sakabe, E. J. Vigmond, M. Munoz, A. Texier, A. Shiroshita-Takeshita, and S. Nattel Mechanisms of atrial fibrillation termination by rapidly unbinding Na+ channel blockers: insights from mathematical models and experimental correlates Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1489 - H1504. [Abstract] [Full Text] [PDF]

				N. Ono, H. Hayashi, A. Kawase, S.-F. Lin, H. Li, J. N. Weiss, P.-S. Chen, and H. S. Karagueuzian Spontaneous atrial fibrillation initiated by triggered activity near the pulmonary veins in aged rats subjected to glycolytic inhibition Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H639 - H648. [Abstract] [Full Text] [PDF]

				P. Coutu, D. Chartier, and S. Nattel Comparison of Ca2+-handling properties of canine pulmonary vein and left atrial cardiomyocytes Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2290 - H2300. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 287/1/H178    most recent 00085.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Miyauchi, Y. Articles by Karagueuzian, H. S. Search for Related Content PubMed PubMed Citation Articles by Miyauchi, Y. Articles by Karagueuzian, H. S.