(Circulation. 1999;100:628-634.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Reflex Control of Sympathetic Activity During Simulated Ventricular Tachycardia in Humans
From the Department of Integrative Physiology, University of North Texas Health Science Center, Ft Worth, Tex (M.L.S., S.L.W.); Division of Cardiology, UT-Southwestern Medical Center, Dallas, Tex (J.A.J., P.J.W., M.H.H., R.L.P.); and Department of Medicine, Case Western Reserve University, Cleveland, Ohio (M.L.S., M.D.C., K.Q.).
Correspondence to Michael L. Smith, PhD, Department of Integrative Physiology, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Ft Worth, TX 76107. E-mail msmith{at}hsc.unt.edu
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Abstract |
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Background—Ventricular tachyarrhythmias present a unique set of stimuli to arterial and cardiopulmonary baroreceptors by increasing cardiac filling pressures and decreasing arterial pressure. The net effect on the control of sympathetic nerve activity (SNA) in humans is unknown. The purpose of this study was to determine the relative roles of cardiopulmonary and arterial baroreceptors in controlling SNA and arterial pressure during ventricular pacing in humans.
Methods and Results—Two experiments were performed in which SNA and hemodynamic responses to ventricular pacing were compared with nitroprusside infusion (NTP) in 12 patients and studied with and without head-up tilt or phenylephrine to normalize the stimuli to either the arterial or cardiopulmonary baroreceptors in 9 patients. In experiment 1, the slope of the relation between SNA and mean arterial pressure was greater during NTP (-4.7±1.4 U/mm Hg) than during ventricular pacing (-3.4±1.1 U/mm Hg). Comparison of NTP doses and ventricular pacing rates that produced comparable hypotension showed that SNA increased more during NTP (P=0.03). In experiment 2, normalization of arterial pressure during pacing resulted in SNA decreasing below baseline (P<0.05), whereas normalization of cardiac filling pressure resulted in a greater increase in SNA than pacing alone (212±35% versus 189±37%, P=0.04).
Conclusions—These data demonstrate that in humans arterial baroreflex control predominates in mediating sympathoexcitation during ventricular tachyarrhythmias and that cardiopulmonary baroreceptors contribute significant inhibitory modulation.
Key Words: nervous system, autonomic • death, sudden • arrhythmia • pressure • pacing
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Introduction |
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Rapid tachyarrhythmias (>250 bpm) result in hemodynamic collapse, are poorly tolerated, and often deteriorate to ventricular fibrillation. In some patients, slower ventricular tachycardia (VT) is also poorly tolerated for reasons that remain unclear. Previously, it was shown that VT or its surrogate, rapid ventricular pacing, provokes increases in sympathetic nerve activity (SNA) related to the degree of hypotension it causes.1 The baroreflex-mediated responses to VT are complex and unique because the brainstem receives conflicting rather than parallel inputs from the 2 major baroreceptor populations: Arterial baroreceptors are unloaded by hypotension, whereas cardiopulmonary baroreceptors are loaded by increased cardiac filling pressures.2 In the previous human study, the degree of maintenance of arterial pressure during sustained VT was related to the magnitude of sympathoexcitation1 ; thus, the net control of SNA by the conflicting inputs to the arterial and cardiopulmonary baroreceptors appears to be important to hemodynamic outcome during VT.
We determined the relative roles of cardiopulmonary and arterial baroreceptors in controlling SNA and arterial pressure during VT simulated by rapid ventricular pacing in humans by comparing the response to hypotension caused by ventricular pacing with that produced by nitroprusside infusion (NTP). In addition, the effect of isolated changes in the stimuli to arterial and cardiopulmonary baroreceptors was evaluated by manipulating either the arterial pressure (with phenylephrine infusion) or central venous pressure (CVP; head-up tilt) during concurrent ventricular pacing.
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Methods |
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Two experiments were performed to examine the relative roles of the cardiopulmonary and arterial baroreceptors in the sympathetic neural and hemodynamic responses to VT simulated by rapid ventricular pacing. In experiment 1, the sympathetic neural and hemodynamic responses to 3 rates of rapid ventricular pacing were compared with 3 doses of NTP in 12 patients referred for diagnostic electrophysiological testing (mean age, 38±3 years). Eight patients were referred for diagnosis and treatment of supraventricular tachycardia; the other 4 were studied for suspected VT. Five patients had known left ventricular dysfunction with ejection fractions <40%. In experiment 2, the sympathetic neural and hemodynamic responses to rapid ventricular pacing with and without either head-up tilt or phenylephrine were studied in 9 patients referred for diagnostic electrophysiological testing (mean age, 45±4 years). Five patients were referred for diagnosis and treatment of supraventricular tachycardia, and 4 were studied for suspected VT. The latter 4 patients had documented left ventricular dysfunction with ejection fractions <40%. Five patients were treated with an ACE inhibitor, and 2 were treated with a diuretic. Three other patients were treated for mild hypertension with a calcium channel blocker, an ACE inhibitor, or combination therapy, including a diuretic. Each patient gave written informed consent for this study, which was approved by the Institutional Review boards of The University of Texas–Southwestern Medical Center, (Dallas, Tex) and University Hospitals of Cleveland (Cleveland, Ohio).
Experimental Design
Experiment 1
We measured SNA, mean arterial pressure (MAP), and
CVP responses during ventricular pacing at 3 pacing cycle
lengths ranging from 300 to 500 ms. Pacing rates were determined by the
patient's hemodynamic tolerance of the pacing so that
a full minute of pacing data could be acquired for each pacing rate
without excessive sustained hypotension. Mean±SEM pacing rates for all
patients were 406±8, 357±6, and 328±7 ms. The responses to pacing
were compared with the responses to 3 doses of NTP (0.2 to 1.0
µg · kg-1 ·
min-1) that produced similar decreases in MAP.
NTP was given to simulate the unloading of arterial
baroreceptors without the significant loading (increased CVP) of
cardiopulmonary baroreceptors produced by
ventricular pacing. Although SNA is usually thought to be
inversely related to diastolic pressure during sinus
rhythm, this does not appear to hold true during rapid
tachyarrhythmias. The SNA and diastolic
pressure responses to VT vary considerably and often do not correlate
significantly during tachyarrhythmias. Therefore, MAP
was used as the primary stimulus for the arterial
baroreceptors in this study.
Experiment 2
We measured SNA, MAP, cardiac filling pressure (as either
pulmonary artery pressure [PAP] or pulmonary
capillary wedge pressure), and cardiac output responses during
ventricular pacing at a cycle length of 400 ms under 3
conditions: pacing alone, pacing plus head-up tilt
(20o to 30o) to a level
that returned cardiac filling pressure to prepacing baseline levels,
and pacing plus phenylephrine infusion sufficient to return
MAP to prepacing baseline levels. Pacing was sustained for 4 to 5
minutes. The role of cardiopulmonary baroreceptors was
evaluated by comparing SNA and hemodynamic data during
pacing with and without head-up tilt in which the cardiac filling
pressure was normalized. Similarly, the role of arterial
baroreceptors was assessed by comparing the responses to pacing with
and without phenylephrine infusion so that the stimulus to
the arterial baroreceptors (arterial pressure)
was normalized.
Measurements
Arterial pressure was measured by use of an
in-dwelling catheter inserted through the femoral artery in all but 3
patients (experiment 2). In those 3 patients, beat-to-beat
arterial pressure was measured noninvasively with a
photoplethysmographic device, and automated cuff pressures were
obtained to corroborate the average beat-to-beat measures from the
photoplethysmographic device. Cardiac filling pressures were measured
in experiment 1 by placing a pigtail catheter in the right atrium
advanced from the femoral vein and in experiment 2 by advancing a
Swan-Ganz thermodilution catheter from the jugular vein to a
pulmonary artery or wedge position. PAP was measured
continuously, and pulmonary capillary wedge pressure was
obtained briefly during each perturbation. Changes in PAP correlated
strongly with the pulmonary capillary wedge pressure
(r=0.98, P<0.0001); therefore, PAPs measured for
the duration of the protocol were used for all analyses. In
experiment 2, cardiac outputs were measured in triplicate by
thermodilution during each condition.
Sympathetic Nerve Recordings
Muscle SNA was measured by a microelectrode inserted into a
branch of the peroneal nerve near the fibular head by standard
microneurographic techniques.3 SNA was identified by its
association with cardiac activity, respiratory activity, and response
to single extra electrical stimuli to the heart. SNA was averaged over
30- to 60-second data segments and quantified from the area under the
curve of sympathetic bursts. Data were normalized for each control
period by determining the average area per burst and assigning that
area a value of 100. Burst areas during the subsequent pacing were
normalized to this standard. Burst area was used because
ventricular pacing often produces broad
arterial pressure oscillations that provoke
broad bursts of sympathetic activity. Under these conditions, burst
amplitude alone does not correlate well with burst area4
and does not account for the prolonged activation of sympathetic nerve
traffic associated with periods of protracted hypotension.
Electrophysiological Techniques
Two or 3 multipolar catheters were introduced
percutaneously into the femoral vein and positioned in
the high right atrium and right ventricular apex as a site
for pacing. Ventricular pacing was performed at a pulse
width of 2 ms and an amplitude twice the diastolic
threshold from the right ventricular apex. A surface ECG
was recorded continuously.
All data were recorded online to a personal computer and were
analyzed post hoc by custom programs. Student's t
test was used for comparisons between pacing and NTP. An ANOVA with a
repeated-measures design was used to compare responses during pacing
with head-up tilt or phenylephrine infusion. Statistical
significance was defined by 
=0.05. All data are presented as
mean±SEM.
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Results |
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The responses to simulated VT were generally consistent among all patients. The pacing rates varied among patients on the basis of individual hemodynamic and symptomatic tolerance of the pacing. Typical responses to VT or its surrogate, ventricular pacing, include an initial decrease in arterial pressure and increase in CVP, which is usually accompanied by an increase in SNA, as shown in Figure 1
. Broad, sustained bursts of SNA
occurred at the onset of pacing when arterial pressure fell
precipitously and was free of noticeable pulsatility. When pacing was
sustained for 
1 minute, arterial pressure usually
returned toward baseline, whereas cardiac filling pressure remained
elevated at a relatively constant level. Sympathetic activity usually
achieved a steady state and then varied with fluctuations in
arterial pressure. In all but 2 patients, SNA increased
above baseline during sustained ventricular pacing; in
those 2 patients, SNA actually decreased modestly (between 4% and
12%) from baseline values that were very high (865 and 981 U/10 s,
respectively, versus 539±97 U/10 s for all patients).
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Experiment 1
The responses to 3 rates of ventricular pacing were
compared in each patient with the responses to 3 NTP rates to produce
similar decreases in arterial pressure. Figure 2 illustrates the average increase in SNA
for a given decrease in MAP caused by 3 pacing rates and 3 NTP rates.
The slope of this relationship was determined for each patient; the
mean slope was greater during NTP (-4.68±1.37) than during
ventricular pacing (-3.36±1.14, P<0.01). The
profile of the baroreceptor stimuli differed between pacing and NTP, as
shown in Figure 3; Figure 3A shows
the responses during graded NTP infusion rates, and Figure 3B
shows the responses during graded rates of ventricular
pacing. The decrease in arterial pressure was uniform
during NTP for systolic and diastolic pressures and
MAP, whereas diastolic pressure tended to be slightly
increased during ventricular pacing. Pulse pressure
decreased more during pacing than during NTP (-38±5 versus
-14±3 mm Hg for the middle NTP dose versus middle pacing rate,
P<0.01). CVP increased during pacing at all pacing rates
(P<0.0001) and decreased slightly during the higher NTP
doses (P<0.05). SNA and CVP data also were compared
between a pacing rate (which produced a mean decrease in MAP of
13.6±2.7 mm Hg) and a 1-minute time segment during NTP in which
MAPs were similar, as shown in the Table (13.2±1.8 mm Hg,
P=0.82). Despite similar decreases in MAP, CVP increased
during ventricular pacing (4.8±0.4 mm Hg) and
decreased during NTP (-1.8±0.5 mm Hg); the difference was
significant (P<0.01). In addition, the SNA increase was
greater (P=0.029) during NTP than during pacing (Figure 4).
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, 3 different NTP rates ranging from
0.2 to 1.0 µg · kg-1 ·
min-1.
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Experiment 2
Responses to ventricular pacing were compared with
pacing and either concomitant infusion of phenylephrine to
normalize MAP or concomitant head-up tilt to normalize cardiac filling
pressure. Figure 5 illustrates the data
for pacing with and without phenylephrine infusion and
head-up tilt. The responses of all variables to pacing in each
repetition (with and without head-up tilt or phenylephrine)
were not different (P>0.47). MAP decreased during pacing
and returned to near baseline levels during phenylephrine
infusion (P=0.23). PAP increased during pacing (16.8±1.1 to
21.2±2.3 mm Hg, P<0.01) and increased
insignificantly more when phenylephrine was infused (to
22.4±2.5 mm Hg, P=0.17). SNA increased significantly
during ventricular pacing (to 189±37% of baseline) and
decreased to below baseline (81±6% of baseline, P<0.05)
during phenylephrine infusion. During pacing and head-up
tilt, PAP was returned to prepacing baseline values by head-up tilt
(17.1±0.9 mm Hg, P>0.05), and SNA increased further
to 212±35% of baseline (P<0.05). MAP decreased slightly
more during head-up tilt and pacing; however, this was not significant
(P=0.09). Cardiac output decreased significantly during
pacing (P<0.05; Figure 6).
Cardiac output did not change during head-up tilt (3.7±0.7 versus
3.4±0.8 L/min) and tended to decrease during phenylephrine
infusion (to 3.1±0.8 L/min), although this difference was not
significant from pacing alone (P>0.05). The estimated total
peripheral resistance increase was predictably greater
during phenylephrine infusion (because of the direct effect
of the vasoactive drug) and was slightly greater during head-up tilt
(Figure 6).
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Significant
difference from ventricular pacing alone
(P<0.05).
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Discussion |
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VT or pacing is followed by a decrease in arterial pressure and an increase in cardiac filling pressures. This presents a unique set of stimuli to the pressure-sensitive baroreceptors: unloading of the arterial baroreceptors to stimulate SNA and loading of the cardiopulmonary baroreceptors to inhibit SNA. In a dog model of VT with previous myocardial infarction and inducible VT, selective denervation of arterial or cardiopulmonary baroreceptors suggested that the arterial baroreceptors play the predominant role in increasing SNA and maintenance of arterial blood pressure, whereas cardiopulmonary baroreceptors appeared to play a modulatory role in these responses.5 Results of the present studies suggest that in patients referred for evaluation of VT or supraventricular tachycardia, arterial baroreceptors play the primary role in producing the sympathoexcitatory response but that this sympathoexcitation is buffered by loading of the cardiopulmonary baroreceptors. The potential physiological mechanisms and clinical implications of these data are discussed below.
Ventricular Pacing as a Model of VT
Ventricular pacing is not a perfect surrogate for the
electrophysiological profile of a
particular VT; the site of origin and the conducting pathways determine
this profile. Although pacing from other sites may produce somewhat
varied hemodynamic outcomes,6 7 these
differences are subtle. Although differences (albeit small) in cardiac
index have been observed, there were no differences in MAP. We have
found that standard pacing from the right ventricular apex
reproduces the hemodynamic and sympathetic neural
responses of septal or anterior wall tachycardias very
consistently in both humans and dogs.1 5 These
previous studies clearly demonstrate that right ventricular
apical pacing is a physiological model of VT and
thus can be used as a clinically relevant surrogate for VT.
Reflex Control of Sympathetic Activity During VT
Under most physiological stressors,
arterial pressure and cardiac filling pressure change in
parallel and thus evoke complementary responses from the
arterial and cardiopulmonary baroreceptors. VT
represents a unique and complex
physiological stressor in that arterial
pressure decreases, often profoundly, while cardiac filling pressures
increase. Thus, the afferent inputs to the brainstem have conflicting
effects on efferent SNA, the principal mediator of reflex control of
circulatory function. Therefore, during VT, 2 fundamental questions
arise: What is the nature of the interaction of these conflicting
inputs, and which reflex mechanism predominates? Two previous studies
addressed this question in dogs using similar paradigms to evaluate the
sympathetic neural responses to rapid ventricular
pacing.5 8 However, the results are not consistent
and may be due to 2 key differences in experimental design. Halliwill
et al8 found that during rapid pacing at 214 bpm, there
was a tendency for a net reduction of SNA, whereas Smith et
al5 showed that SNA increased during
ventricular pacing or tachycardia at 220 to 280
bpm and that this response was eliminated by arterial
baroreceptor denervation. Halliwill and colleagues studied healthy dogs
in an open-chest preparation, whereas Smith et al studied dogs in a
closed-chest preparation. Thoracic surgery produces a significant
stress to the animal that is known to produce large increases in basal
sympathetic activity; thus, a likely explanation for the differing
responses of these 2 studies was that basal activity was extremely high
in the Halliwill et al study, thereby favoring a
sympathoinhibitory response.
Although the same reflex mechanisms are operational in humans, there is evidence that cardiopulmonary baroreflex mechanisms operate somewhat differently in humans, probably because of the predominant upright posture of humans. For example, the Bainbridge reflex (observed in several species), which produces significant cardiac acceleration with increased atrial pressure in many animal species, appears to be negligible in humans.9 10 The present study was designed to address similar questions regarding arterial versus cardiopulmonary control of SNA and arterial pressure during ventricular pacing in humans. In this study, ventricular pacing at 120 to 200 bpm usually resulted in elevations in SNA, although the magnitude of this response varied widely. Two patients with very high basal SNA demonstrated a sympathoinhibitory response during ventricular pacing. This is consistent with our interpretation of the results of Halliwill et al8 : A high basal sympathetic activity favors an inhibitory response. Nevertheless, these data are consistent with a previous study that showed that ventricular pacing or VT usually produces a significant sympathoexcitatory response in humans.1
In the present study, we addressed the question of how SNA is
controlled in humans under these conditions of conflicting inputs. In
experiment 1, we found that a comparable decrease in
arterial pressure, without an increase in CVP, produced a
greater sympathoexcitatory response. These data
also suggest that cardiopulmonary baroreceptors may impart an
inhibitory effect because the increase in SNA was greater
when CVP was not increased. However, this is a guarded conclusion
because CVP tended to decrease slightly during NTP. This decreased CVP
would be expected to unload the cardiopulmonary baroreceptors
and potentially increase SNA.11 In experiment 2, we used 2
conditions to normalize the stimulus to either arterial
baroreceptors (by returning arterial pressure to prepacing
baseline with infusion of phenylephrine) or
cardiopulmonary baroreceptors (by decreasing cardiac filling
pressure back to prepacing baseline with head-up tilt). Normalizing
arterial pressure resulted in SNA decreasing below
baseline. These support the conclusion that the cardiopulmonary
baroreceptors contribute a significant inhibitory
modulation of SNA. Furthermore, when cardiac filling pressure was
normalized by head-up tilt, SNA increased 
20% more. This occurred
without a significant change in arterial pressure; thus,
these data provide the most compelling evidence that
cardiopulmonary baroreceptors impart a modest modulatory effect
during simulated VT. In each experimental paradigm, we were unable to
control the stimuli to the 2 baroreceptor populations perfectly, but
the responses were consistent among the different conditions
and strongly support the conclusion of our previous study in dogs that
arterial baroreceptors play the primary role in mediating
sympathetic neural responses to ventricular
tachyarrhythmias and are modulated importantly by
cardiopulmonary baroreceptors.5
Why does the net effect usually favor arterial baroreflex–mediated sympathoexcitation rather than cardiopulmonary baroreflex–mediated sympathoinhibition? During orthostatic stress, cardiopulmonary baroreceptors clearly play an important role in increasing SNA11 12 and producing vasoconstriction.13 Cardiopulmonary baroreceptor loading also produces sympathoinhibition14 and peripheral vasodilation.13 15 The magnitude of increased cardiac filling pressures is often greater during VT than that usually imposed by volume loading or leg raising used in previous studies; thus, it would be expected that the cardiopulmonary baroreflex would impart significant sympathoinhibition. In addition, cardiopulmonary unloading has been shown to enhance arterial baroreflex gain in the control of heart rate and vascular resistance, and these studies implied that cardiopulmonary loading would inhibit arterial baroreflex gain.16 17 18 In the face of these inhibitory effects, it appears that the balance of the stimuli during VT, unloading of arterial baroreceptors and loading of cardiopulmonary baroreceptors, is weighted toward the effects of the arterial baroreflex. The initial hypotension at the onset of VT is very profound and typically remains much greater than the elevation of cardiac filling pressures. Therefore, our data suggest that this hypotension produces a much greater sympathoexcitation than the sympathoinhibition produced by the increase in CVP. Despite the predominance of the arterial baroreflex to produce sympathoexcitation, our data also show that cardiopulmonary baroreflex inhibition does occur and can play a significant modulatory role. One reason that a greater effect was not observed could be that many patients had impaired cardiopulmonary baroreflex function. Several studies have shown that cardiopulmonary baroreflex function is impaired in patients or animals after myocardial infarction with left ventricular dysfunction or congestive heart failure.19 20 21
Clinical Implications
Several factors contribute to the hemodynamic
outcome of a VT, including ventricular rate, left
ventricular pump function, and reflex sympathetic
activation. Each plays a role, yet it remains unclear how important
each is in determining the net outcome. Previously, we developed a
predictive model based on data from 16 patients that suggested that
each factor plays an important role.1 The present
study, together with our previous studies,1 5 suggests
that normal reflex-mediated sympathetic activation is beneficial during
VT by helping to maintain stable hemodynamic status. We
predict that in patients with significantly impaired
arterial baroreflex function, the prognosis for stable
hemodynamic responses to VT is poor. Impaired
arterial baroreflex function has been shown to correlate
with increased risk of ventricular arrhythmias and
mortality.22 23 24 Is this a causal relation? If so, what is
the mechanism? The answers to these questions are unknown; however, we
speculate that a mechanism for this increased risk involves impaired
reflex support of arterial pressure during VT, a common
precursor to ventricular fibrillation. It is clear that
poor hemodynamic tolerance of VT is often accompanied
by a downward spiral to polymorphic VT and ventricular
fibrillation. This is consistent with the observation that
patients with heart failure do not tolerate VT well and often die from
sudden cardiac death when VT occurs.25
Conclusions
In conclusion, these data are generally consistent with
the findings in the previous dog study that arterial
baroreflex control predominates in mediating sympathoexcitation during
VT. Cardiopulmonary modulation during VT functions to inhibit
SNA and appears to play a greater role in humans. The net importance of
these reflex mechanisms in determining hemodynamic
stability during VT is still not clear; however, preliminary results
from our laboratory suggest that arterial baroreflex gain
is predictive of hemodynamic outcome.
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Acknowledgments |
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This research was supported in part by Grants-in-Aid from the Northeast Ohio and Texas affiliates of the American Heart Association and by grant HL-49266 from the National Heart, Lung, and Blood Institute.
Received October 21, 1998; revision received April 28, 1999; accepted May 19, 1999.
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