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Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Although the atrioventricular node (AVN) plays a vital role in blocking many of the atrial impulses from reaching the ventricles during atrial fibrillation (AF), a rapid irregular ventricular rate nevertheless persists. The goals of the present study were to explore the feasibility of novel epicardial selective vagal nerve stimulation for slowing of the ventricular rate during AF and to characterize the hemodynamic benefits in vivo. Electrophysiological-echocardiographic experiments were performed on 11 anesthetized open-chest dogs. Hemodynamic measurements were performed during three distinct periods: 1) sinus rate, 2) AF, and 3) AF with vagal nerve stimulation. AF was associated with significant deterioration of all measured parameters (P < 0.025). The vagal nerve stimulation produced slowing of the ventricular rate, significant reversal of the pressure and contractile indexes (P < 0.025), and a sharp reduction in one-half of the abortive ventricular contractions. The present study provides comprehensive evidence that slowing of the ventricular rate during AF by selective ganglionic stimulation of the vagal nerves that innervate the AVN successfully improved the hemodynamic responses.
ventricular rate; epicardial fat pads; localized nerve stimulation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ATRIAL FIBRILLATION (AF) has been long recognized as one of the most frequent chronic arrhythmias. Although the restoration and maintenance of normal sinus rhythm is the ultimate goal, it is frequently unachievable. Therefore, ventricular rate (VR) control during AF remains the only realistic long-term solution in a majority of patients (15). Normally, the atrioventricular node (AVN) plays a vital role in blocking many of the rapid atrial impulses from reaching the ventricles. However, this filtering property of the AVN is insufficient to prevent a rapid irregular VR from being elicited during AF. Although drugs are generally used to depress the AVN conduction and thus to control the VR, the use of drug therapy for this purpose is limited by the lack of efficacy in some patients and intolerability due to side effects in others (7, 15). Recently, slow pathway modification via discrete lesions in the posterior approaches has been developed to achieve slower VR while preserving the AVN. This technique showed some encouraging clinical results in drug refractory AF patients, but with inconsistent success rates (15-76%) among different investigators and with recurrence of rapid VR in up to 25% of cases (10, 21).
The conduction through the AVN is normally altered by changes in the autonomic control of the heart (32). Many investigators (2, 5, 6, 11, 12, 14, 17, 23-26) have shown that stimulation of parasympathetic nerves, which selectively innervate the AVN, further delays conduction through the node. A recent in vitro study by Mazgalev et al. (20) found that vagally induced slowing of the VR during AF is feasible by using postganglionic endocardial nerve stimulation in rabbits. Similarly, activation of these parasympathetic nerves via endocardial stimulation has resulted in slowing of VR during AF in dogs (28). However, these studies did not evaluate the hemodynamic consequences of vagally induced ventricular slowing. Furthermore, the anatomic basis of the epicardial approach for selective parasympathetic stimulation has been well established in animal models, and also has been reported in humans (5). Therefore, the goals of the present study were to expand the currently available information by exploring the feasibility of epicardial selective nerve stimulation for slowing of the VR during AF, and by characterizing the hemodynamic benefits of vagally slowed VR in vivo.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The experimental protocol was approved by the Animal Research Committee of the Cleveland Clinic Foundation. All experimental procedures were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Surgical preparation. Eleven adult mongrel dogs (23-30 kg body wt) were premedicated with thiopental sodium (20 mg/kg) intravenously and intubated and ventilated with room air supplemented with oxygen as needed to maintain normal arterial blood gases by a respirator (Narkomed 2, North American Drager; Telford, PA). Anesthesia was then maintained with 1-2% isoflurane throughout the experiment. The left external jugular vein was cannulated to infuse normal saline solution at 100-200 ml/h to replace spontaneous fluid losses. Standard surface electrocardiogram (ECG) leads (I, II, and III) were monitored continuously throughout the entire study. Intermittent arterial blood gas measurements were taken and ventilator adjustments were made to correct any metabolic abnormalities. A rectal probe was used to monitor rectal temperature. An electrical heating pad was then placed under the animal and operating-room lamps were used to maintain a body temperature of 36-37°C.
The right femoral artery was cannulated and a micromanometer-tipped catheter pressure transducer (Millar; Houston, TX) was inserted and advanced into the thoracic aorta near the aortic valve to monitor systemic blood pressure. Another Millar catheter was inserted through left carotid artery and advanced so that the tip was in the left ventricle (LV) to record LV pressure. Before being inserted, both catheters were soaked in warm saline solution for 30 min and precalibrated. After a median sternotomy was performed, a pericardium cradle was created to support the heart. Custom-made Ag-AgCl quadripolar plate electrodes were sutured to the high right atrium and right ventricular apex for bipolar pacing and recording (Fig. 1). Similar bipolar plate electrodes were also sutured to two epicardial fat pads (Fig. 1) that contain parasympathetic neural pathways selectively innervating the sinus node (SN) and the AVN, respectively (24). The SN fat pad was located at the right pulmonary vein atrial junction. The AVN fat pad was located at the junction of inferior vena cava and the left atrium. The ascending aorta was isolated and a flow-probe (16 or 20 A) was placed around it and connected to a flowmeter (model HT 207, Transonic System; Ithaca, NY) to measure aortic blood flow. All signals (surface ECGs, right atrial and ventricular electrograms, arterial blood pressure, LV pressure, and aortic flow) were amplified, filtered, digitized, and continuously displayed on a monitoring system (Prucka Engineering). In addition, these signals along with calibration signals were simultaneously recorded on magnetic tape (model 4000A, Vetter Digital) for later computer analysis with the use of an AxoScope (Axon Instruments) and custom software programs.
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Electrical stimulation. A programmable eight-channel stimulator (Master-8, AMPI) was used to generate the desired sequence of rectangular impulses for atrial pacing or nerve stimulation. The amplitude of the impulses (in mA) was determined by current isolators (model A360, WPI) that also permitted alternation of the polarity of the impulse to reduce the effects of polarization at the electrode-tissue interface.
Study protocol. After the surgical procedures were completed, each study consisted of three periods. First, a stabilization period of 30 min at normal sinus rhythm was allowed before all baseline hemodynamic values (surface ECG, right atrial and ventricular epicardial ECGs, aortic pressure, LV pressure, and aortic flow) were collected. During this period, the R-R intervals were automatically measured online by a computer and the average (±SD) of 100 consecutive sinus intervals was determined. Second, AF was induced by a two-step maneuver. AF was initiated by brief burst (5-10 s) of right atrial pacing (5-10 mA, 1-ms pulses at 20 Hz) and maintained by SN fat-pad stimulation (4-7 mA, 50-µs pulse duration at 20 Hz), which provided selective vagal stimulation to the SA node and surrounding atrium. Note that SN fat-pad stimulation did not capture the atrium. In this fashion, AF could be maintained for many hours and in some cases spontaneous AF persisted even when the supporting vagal stimulation was withdrawn. After a period of AF stabilization of at least 15 min, a new set of electrical and hemodynamic recordings was made. Third, while still maintaining the AF, the VR was slowed by AVN fat-pad stimulation. Although such stimulation can affect both pre- and postganglionic structures, it is assumed that the former have a lower threshold of activation (3, 18). Because the neurotransmitter release resulting from this pre- and postganglionic vagal stimulation (VS) is mainly limited to the AVN region, the abbreviation AVN-VS will be used to describe this modality. AVN-VS was started at a low stimulator output of <3 mA at 20 Hz and 50 µs pulse duration. Because hemodynamics are dependent on heart rate during AF and because it is presumed that they are best at a rate close to the sinus rate (19), the amperage of stimulation was adjusted until the average heart rate response was slowed to the previously determined sinus rate. Notably, due to the very short duration of the nerve pulses and their relatively low intensity, the AVN-VS never resulted in capturing of the nearby ventricular myocardium. The term "subthreshold" used in the text is therefore applied to indicate that the nerve stimulation was not accompanied by direct ventricular pacing. After stabilization of the slowed rate (10-15 min), a third set of electrical and hemodynamic data was collected (AF + AVN-VS).
Data acquisition and analysis. The tape-recorded data were played back off line and digitized at a rate of 1 kHz-per-channel by AxoScope (Axon Instruments). The R-R intervals, systolic and diastolic aortic blood pressures, peak LV systolic pressure (LVSP), end-diastolic pressure (LVEDP), and stroke volumes (SV) were measured beat by beat by a custom-made software for each period of recording. The LV first time derivative of LV pressure (dP/dt) was derived from LV signal. To determine the SV (in ml), the aortic flow signal from the probe (in l/min) was time integrated for the duration of each cardiac cycle (in ms). Cardiac output was then calculated as a product of the average SV and heart rate. The SV and the cardiac output determined in this fashion represented the total LV outflow minus coronary flow. All hemodynamic measurements were averaged for at least 100 ventricular cardiac cycles after stable average heart rate had been achieved. Preliminary experiments showed that samples with such duration permit correct evaluation of the measured parameters. The number of "abortive beats" was also determined in each step of the protocol. These were beats for which ventricular depolarization occurred, but the subsequent contraction was insufficient to open the valve and produce aortic flow. Naturally, such beats were associated with short ventricular coupling intervals, such as those present during AF. A given beat was classified as abortive if the corresponding SV was <1 ml.
Echocardiographic measurements.
Epicardial echocardiography was performed using commercially available
equipment (Sequoia model C512, Acuson; Mountain View, CA) with a
3.5-MHz phased-array transducer. The LV end-diastolic (EDV) and
end-systolic (ESV) volumes were measured by single plain Simpson's
rule (9). From the volumes obtained, LV ejection fraction
(EF) was calculated as EF = (EDV 
ESV)/EDV × 100 (%).
Statistical analysis. Data are expressed as means ± SD. Hemodynamic differences during sinus rhythm, AF, and AF + AVN-VS were evaluated with an analysis of variance (ANOVA). If the ANOVA revealed significance, it was followed by multiple comparisons with Bonferroni correction. Abortive beats during the AF and AF + AVN-VS periods were compared using a paired Student's t-test. For single comparison, a value of P < 0.05 was required for statistical significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Neural effects of epicardial stimulation of fat pads.
Figure 2 illustrates that during sinus
rhythm (cycle length of 490 ms and AVN conduction time of 150 ms; Fig.
2A), stimulation of the SN fat pad produced strong
chronotropic effect (cycle length of 1,180 ms; Fig. 2B) that
was associated with a shortening of the AVN conduction time (130 vs.
150 ms). The dromotropic effect of this vagal stimulation was complex.
It depended on such indirect factors as the prolongation of the cycle
length and a possible shift of the sinus pacemaker (30). A
direct effect via nerve fibers innervating the AVN and affected by the
SN fat-pad stimulation could not be ruled out. Previous reports (see,
e.g., Ref. 23) described such anatomic aberration, when
preganglionic parasympathetic nerve projections to the AVN pass in
close proximity to the right pulmonary vein fat pad. Pacing the atria
at a constant cycle length tested the direct effect of the SN fat pad.
It was found to be present in 2 of 11 animals (see Induction and
maintenance of AF).
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Induction and maintenance of AF. AF was inducible in all 11 dogs by rapid right atrial pacing. Although continuous rapid right atrial pacing could be used to maintain AF over a prolonged period of time, large pacing artifacts were frequently present in some electrical signals. Subthreshold stimulation of the SN fat pad, presumably by shortening the refractoriness of the atrial tissues surrounding the SA node and by increasing the overall dispersion (6, 33), successfully maintained AF in 8 of 11 dogs while permitting "clean" recording traces (Fig. 2D). In two of the eight dogs, stimulation of the SN fat pad, while successfully maintaining the AF, also affected the AVN and thus the VR. Finally, in the remaining three dogs, the SN fat-pad stimulation required suprathreshold amplitudes resulting in atrial capture. Therefore, in the latter five animals, AF was maintained by high-rate right atrial pacing.
Selective AVN-VS during AF. Notably, AVN-VS had no apparent effect on the ongoing AF. That is, both the frequency and waveforms of atrial electrograms during AF did not appear to change when AVN-VS was applied. However, the reduction of VR started immediately (within seconds) after AVN-VS was initiated (Fig. 2D) and terminated abruptly after its cessation. The magnitude of these responses was dependent on the stimulation intensity and varied among animals. The average AVN-VS amplitude was adjusted to bring the heart rate to the sinus rate level, that is, the average amperage was 6.3 ± 2.4 mA (range 1.5 to 10 mA). Because the pulses were very short (50 µs), neither the atria nor the ventricles were excited even at the highest amperage levels used.
Hemodynamic measurements during sinus rhythm, AF, and AF + AVN-VS.
Figure 3 shows the changes in consecutive
R-R intervals observed in one of our experiments during the three
periods of the study protocol. The left 100 cardiac cycles were
recorded during sinus rhythm at regular R-R intervals of 460 ms (130 beats/min). AF resulted in rapid and irregular ventricular responses
compared with that found during sinus rhythm (the middle 200 beats).
That is, the average R-R interval was 250 ms (240 beats/min). Local stimulation of the AVN fat pad (selective parasympathetic ganglionic stimulation to AVN) prolonged the R-R intervals to an average of 465 ms, a VR of 129 beats/min (the selection of the right 200 beats). With
this increased average R-R interval, there was a corresponding increase
in its variation during the VS.
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Composite hemodynamic responses.
The hemodynamic responses in 11 experiments during sinus rhythm, AF,
and AF + AVN-VS are summarized in Table
1. In addition to the average R-R
interval, the variability of consecutive cardiac cycles was evaluated
in each animal. Thus, the R-R interval variability measured on
beat-by-beat basis during sinus rate was only 0.28% of the average
cardiac cycle, whereas during AF it increased to 15.93% (compare with
Fig. 3). During AF + AVN-VS there was a prolongation of the
average R-R interval (Table 1, 485 ms) along with an increased beat-by-beat variability of 26.64%.
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LV dP/dt.
Furthermore, the increased rate was accompanied by high presence of
abortive beats during AF (41%), resulting in reduction of the average
stroke volume compared with sinus rhythm (17.7-8.9 ml,
P < 0.025). Despite the increased VR, this marked
reduction in stroke volume led to a significant reduction in cardiac
output (2.2-1.7 l/min, P < 0.025).
These reductions in LV function during AF (compare hemodynamic
measurements in middle vs. left columns in Table 1) were substantially reversed by concurrent application of local VS to the AVN (compare hemodynamic measurements in right vs. middle columns in Table 1). In
particular, whereas the systolic and diastolic aortic blood pressures
significantly decreased as the result of depressed ventricular function
during AF, the localized AVN-VS reversed these trends of both aortic
pressures back toward the values observed during sinus rate. Similarly,
significant improvements were documented in LVSP, ± LV
dP/dt, and SV (P < 0.025). The cardiac
output was increased and the LVEDP decreased even though the trend did
not reach statistical significance.
Echocardiographic results.
Successful echo evaluations were performed in parallel with the
electrophysiological protocol in five of these acute experiments (Table
2). The LV EF significantly decreased
during AF (P < 0.025) along with the significant
decrease in the LV end-diastolic volume (LVEDV) and LV end-systolic
volume (LVESV) (P < 0.025) compared with those at the
baseline sinus rhythm. Note that despite the decrease in the LVEDV, the
corresponding LVEDP (Table 1) was increased, suggesting decreased LV
compliance. During AVN-VS, LV EF increased significantly
(P < 0.025) along with the significant increase in the
LVEDV and LVESV (P < 0.025), compared with AF alone.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Major findings. The first major finding of this study is that one can rapidly and reversibly control VR during AF via a selective stimulation of the epicardial parasympathetic nerves that project to the AVN. Second, with this mode of controlling of VR, an improvement in hemodynamics is achieved, although a complete return to normal values (as in sinus rate) was not obtained. Third, in this study, we demonstrated that VS through right pulmonary vein fat pad could maintain AF once it was induced. This mode of stimulation could be served as an animal model of vagal facilitation of AF.
In summary, the induction of AF resulted in rapid irregular R-R intervals and the high presence of abortive beats during AF, which resulted in an average reduction of the stroke volume compared with sinus rhythm. Despite the increased VR during AF, there was a significant reduction in cardiac output. The reduction in myocardial performance led to reduced peak LVSP, +LV dP/dt, andLV
dP/dt, whereas LVEDP increased. The LV EF significantly
decreased during AF along with the significant decrease in the LVEDV
and LVESV compared with those at the baseline sinus rate.
The present study provides evidence that selective epicardial AVN VS
improves hemodynamics during AF. That is, significant improvements were
documented in LVSP, ±LV dP/dt, and SV. LV EF was increased
significantly along with the LVEDV and LVESV compared with AF when the
vagal stimulation to the AVN was applied.
The presence of atrial synchronized contractions, which could
contribute to the ventricular filling, was lacking during both AF alone
and AF with concomitant AVN-VS. However, the slowing of VR by VS
increased the LV volume and thus the preload of the heart (Table 2).
This could be one of the major factors in improving the hemodynamic
responses observed in the present study.
AVN nerve stimulation as an alternative tool for VR control during AF. The failure of consistent anatomic modification of the AVN via limited ablation lesions leaves complete nodal destruction as the remaining alternative therapy. This makes the patient permanently dependent on the pacemaker to provide adequate VR control after an irreversible total ablation of the AVN. Moreover, the pacing produces an undesirable alteration of the normal sequence of ventricular depolarization. It would be preferable to achieve VR slowing during AF without inflicting a permanent damage to the AVN, thus preserving also the anterograde ventricular activation. Because of the limitations and drawbacks of the current available treatments, new treatment options such as the one tested in this study deserve attention.
Because AVN plays a vital role in blocking many of the atrial impulses and subsequently slowing VR in AF, one attractive idea is to take advantage of the rich supply of vagal nerves to the nodal region. If these nerves can be selectively stimulated, then a majority of atrial impulses would be blocked within the AVN and slowing the VR to a more tolerable level would be achieved. Mazgalev et al. (20) demonstrated this principle and elucidated the mechanism of parasympathetic modification of the AVN during AF in vitro. These rabbit heart studies were designed to test the theoretical hypothesis that vagally induced slowing of the VR during AF is feasible. We were able to show that brief bursts of subthreshold (for the myocardium) postganglionic VS produced hyperpolarization of the AVN fibers that led to depressed conduction and a substantial prolongation of the ventricular (R-R or His-to-His) intervals during simulated AF. These effects were dependent on the intensity of the postganglionic VS and the frequency of its application, although the amplitude of the stimulation current remained below the threshold of excitation of the cardiac tissue. It should be noted that vagal modulation of the AVN conduction during AF might also involve alterations in the atrio-nodal engagement, although direct evidence for vagally induced effects on the inputs to the AVN during AF is not available.Historical perspective. For more than 100 years, scientists have stimulated the peripheral cervical vagi (preganglionic parasympathetic nerve fibers) that innervate the heart. This stimulation results in overall negative chronotropic, dromotropic, and inotropic responses. The cell bodies of the postganglionic parasympathetic nerve fibers, which selectively innervate limited nodal regions or the ventricles of the heart, have been identified for both animals and humans (2, 5, 6, 8, 11-14, 17, 23-26).
Mazgalev et al. (20) found that vagally induced slowing of the VR during AF is feasible via endocardial nerve stimulation. Recent in vivo experiments (28, 29) utilized an endocardial approach (superior vena cava, coronary sinus, or the right pulmonary artery) and demonstrated vagally mediated slowing of VR during AF. Ali et al. (1) reported that stimulating the right atrial ventral ganglionated plexus in dogs resulted in slowing of VR during supraventricular tachycardia, along with an improvement in arterial and LV pressures. In this study, the nerve stimulation affected the sinus nodal and possibly other regions of the heart besides the AVN (22). Until now, no complete study of the systemic hemodynamic effects produced by selective AVN parasympathetic stimulation during AF has been reported.Study limitations. First, certain limitations are imposed by the design of these acute open-chest experiments that required anesthesia and maintenance of AF by SN fat-pad stimulation. Furthermore, whether the selective AVN vagal stimulation has a prolonged effect on the hemodynamics during AF needs evaluation. Some studies (27) have reported the so-called "fading effect." The latter refers to the gradual reduction in the degree of heart rate slowing that is typically observed in in vitro experiments. The underlying mechanism could be the limited supply of choline in vitro that is needed for acetylcholine synthesis (4, 31). Indeed, a report by Schauerte et al. (28) suggested stable ventricular slowing in an open-chest dog model over a period of 20 h. Nevertheless, chronic studies are needed to evaluate the effects of AVN-VS in conscious subjects under conditions of spontaneous AF, normal basic autonomic tone, and during exercise.
Second, the present study used an epicardial as opposed to an endocardial approach to selectively stimulate the parasympathetic nerves that innervate the AVN. At this point, it is difficult to predict which approach may be preferable. A major advantage of the former is the lower required intensity, probably due to delivery of stimulation directly at the nerve fibers. Low intensity has the benefit of prolonging the life of potential implantable devices. More importantly, it may reduce the risk of side effects such as discomfort and/or pain. With a typical impedance of 1,000
, the AVN-VS impulses
in our experiments were ~5 V, which is several times less than when
the endocardial basket electrode was used (28).
Multiple-pole catheter stimulation has been applied to conscious human
subjects in an electrophysiological catheterization laboratory but the
practice was abandoned because these patients expressed discomfort
(A. L. Waldo, personal communication). Conscious experiments are
needed to evaluate the risks of concomitant afferent nerve stimulation
that could evoke pain.
Third, further efforts are needed to establish the mechanisms
underlying the variability of the R-R intervals observed in this study
and to determine ways for regularization of the rhythm. It would be
desirable to explore the feasibility for a controlled beat-to-beat
delivery of VS to achieve a predetermined VR slowing and avoid
excessively long R-R intervals.
Currently, one might assume that the epicardial approach would require
extensive open-chest surgery and could only be justifiably applied in
some postoperative patients with AF. However, with the development of
new technologies, it may become a viable option. For example, a
transcutaneous approach for epicardial ablations is presently being
used and may provide the means for selective epicardial nerve
stimulation (16).
In conclusion, the present study provides comprehensive evidence that
slowing of the VR during AF by selective epicardial ganglionic
stimulation of the vagal nerves innervating the AVN successfully
improved the hemodynamic responses. Further studies are needed to
elucidate the optimal parameters for delivery of this new modality and
to evaluate its long-term effects.
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ACKNOWLEDGEMENTS |
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The authors thank Deborah A. Agler and Don G. Hills for expert assistance during the echocardiographic studies and for the surgical preparations.
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FOOTNOTES |
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This study was supported in part by American Heart Association Grant AHA-9808489A and by National Institutes of Health Grant RO1 HL-60833-01A1.
Address for reprint requests and other correspondence: T. N. Mazgalev, Research Institute FF1-02, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195 (E-mail: mazgalt{at}ccf.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.
Received 12 April 2001; accepted in final form 21 June 2001.
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METHODS
RESULTS
DISCUSSION
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, Bipolar stimulating electrodes; SVC, superior vena
cava; HRA, high right atrium; PA, pulmonary arteries; Ao, aorta; RPV,
right pulmonary veins; LPV, left pulmonary veins; SN, sinus node; AVN,
atrioventricular node; IVC, inferior vena cava; RV, right ventricle;
LV, left ventricle.
