Download Point:Counterpoint: Respiratory sinus arrhythmia is due to a central

J Appl Physiol 106: 1740 –1744, 2009;
doi:10.1152/japplphysiol.91107.2008.
Point:Counterpoint
Point:Counterpoint: Respiratory sinus arrhythmia is due to a central
mechanism vs. respiratory sinus arrhythmia is due to the baroreflex
mechanism
POINT: RESPIRATORY SINUS ARRHYTHMIA IS DUE TO A
CENTRAL MECHANISM
1740
8750-7587/09 $8.00 Copyright © 2009 the American Physiological Society
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Blood pressure and heart periods fluctuate at respiratory
frequencies in healthy humans. Some researchers (8, 23) explain this as a cause-and-effect relation: blood pressure changes
trigger baroreflex-mediated R-R interval changes. Here I make the
case that respiratory sinus arrhythmia is a central phenomenon
that is independent of blood pressure changes. I base this argument on several well-documented physiological facts.
Vagal-cardiac motoneuron membrane potentials fluctuate at
respiratory frequencies (16), modulate responsiveness of vagal
motoneurons to arterial baroreceptor inputs (12, 13), and impose a respiratory rhythm on vagal-cardiac nerve traffic and
heart periods (18). Central respiratory gating of vagal motoneuron responsiveness (11) is sufficient to explain respiratory
sinus arrhythmia.
The cascade of events comprising a vagal baroreflex response does not play out instantaneously; each step in the
sequence takes time. Therefore, a critical question is, how
much time is required between the beginning of the cascade
sequence, a change of arterial pressure, and the end of the
sequence, a change of heart period?
Latencies of individual components of vagal baroreflex responses have been measured directly in animals and include
transduction of baroreceptive artery stretch into baroreceptor
firing, 18 ms (19); polysynaptic central transactions, 26 ms
(21); transmission of vagus nerve traffic from the brain stem to
the sinoatrial node, 2 ms (6); and sinoatrial node responses, 120
ms (6). Simple addition of these latencies (14) yields a vagal
baroreflex arc latency of 166 ms; the great majority of this
latency, 72%, reflects the kinetics of sinoatrial node responses
to released acetylcholine.
These animal data comport well with results obtained with
electrical carotid sinus nerve stimulation and abrupt intense
neck suction in humans. Minimal human vagal baroreflex
latency is remarkably short—less than 0.5 s (5, 25), and
possibly as short as 0.24 s (9). However, the operative word in
the preceding sentence is “minimal”; data derived from highly
unphysiological experimental interventions do not necessarily
answer the question, what is vagal-cardiac baroreflex latency in
the arterial pressure, heart period transactions that occur in
everyday life? The short answer to this question is this: vagal
baroreflex responses do not occur instantaneously—they take
time. The question then becomes, how much time?
In one of the earliest quantitative studies of human vagal
baroreflexes, Smyth, Sleight, and Pickering (27) gave intravenous bolus injections of angiotensin, and plotted heart period
responses as functions of preceding arterial pressure increases.
They reported that the best linear fits were obtained when each
systolic pressure during the pressure rise was correlated with
the R-R interval of the heart beat that followed the pressure
pulse. In 1986 (15), we confirmed this observation and showed
that most spontaneously occurring baroreflex sequences (3)
yield the highest correlation coefficients when each arterial
pulse is related to the following R-R interval.
When baroreceptors are stimulated with abrupt intense neck
suction, the time from the onset of the stimulus until the
maximum P-P interval prolongation averages 1.5 s (2). (In a
subject with a P-R interval of 0.15 s, the stimulus to R wave
latency becomes 1.65 s.) Wallin and Nerhed (29) signal averaged arterial pressures and R-R intervals on the peaks of
muscle sympathetic bursts and reported that diastolic pressure
rises after sympathetic bursts and R-R intervals peak between
1.8 and 4.8 s (average, 2.9) later.
The next question is, what is the latency between respiratory
frequency arterial pressure and R-R interval changes? We
performed cross-spectral analysis of systolic pressures and R-R
intervals in two studies (7, 20), the results of which are
summarized in Fig. 1.
Data in Fig. 1, A and B, were recorded during fixedfrequency breathing at progressive angles of passive upright tilt
(7). The average phase angle was minus 53° at the low
frequency (A) and did not change significantly during tilt (P ⫽
0.48, linear regression). Such analyses do not indicate whether
systolic pressure changes precede R-R interval changes [by
1.6 s (53°/360°䡠11.1 s)] or follow R-R interval changes [by 9.5
(11.1 ⫺ 1.6) s]. A latency of 9.5 s is not consistent with
baroreflex mechanisms; systolic pressure returns to usual levels
within 3 s after transient reductions of arterial pressure (30).
Therefore, it is likely that low frequency R-R interval changes
follow systolic pressure changes, with an average latency that
is consistent with arterial baroreflex physiology (2).
Figure 1B shows an entirely different picture for respiratoryfrequency systolic pressure—R-R interval phase angles. The
phase was positive in the supine position (extreme left) and
declined systematically (P ⫽ 0.001) to negative levels, in
proportion to the tilt angle. Average calculated latencies between systolic pressure and P-P intervals (subtracting an assumed P-R interval of 0.15 s) from these data were plus 0.3 s
in the supine position and minus 0.1 s at the 80° the tilt
position. Other studies (8, 23) document similar latencies for
both low- and respiratory-frequency systolic pressure-R-R interval cross-spectra in supine subjects.
Data shown in Fig. 1, C and D, (20) were recorded from
supine subjects during controlled-frequency breathing and conventional mechanical ventilation (both at 0.25 Hz). Calculated
latencies averaged ⫺2.7 and ⫺3.0 s at low frequencies (P ⫽
0.88, Mann-Whitney Rank Sum, Fig. 1C) and ⫺0.28 and 0.53 s
at respiratory frequencies (P ⫽ 0.001, Fig. 1D) during spontaneous breathing and mechanical ventilation. One point that
stands out in this figure [and in other studies (4, 7, 10, 24)] is
that systolic pressure-R-R interval phase angles at respiratory
frequencies vary greatly.
Therefore, if respiratory frequency R-R interval fluctuations
are baroreflex-mediated, baroreflex latencies—mainly reflecting the kinetics of acetylcholine effects on the sinoatrial
node—vary systematically, according to the physiological cir-
Point:Counterpoint
1741
cumstances of the moment. Saul and coworkers (24) proposed
a vastly simpler explanation: R-R interval changes follow breathing, not pressure, with a nearly fixed time delay of ⬃0.3 s.
Although I emphasize baroreflex latencies, other types of
evidence point to a respiratory, non-baroreflex causation of
respiratory R-R interval changes. In anesthetized dogs, R-R
interval fluctuations follow phrenic nerve activity and persist
when intrathoracic pressure fluctuations are abolished (26).
Thoracotomy increases respiratory blood pressure changes but
decreases R-R interval fluctuations (17). Fixed-rate atrial pacing reduces respiratory frequency blood pressure fluctuations
(28); if baroreflex responses buffer blood pressure fluctuations,
blood pressure oscillations should be greater, not less, during
fixed-rate pacing. Conventional mechanical ventilation, which
presumably silences phrenic motoneurons, augments respiratory blood pressure fluctuations, but nearly abolishes respiratory R-R interval fluctuations (20). Removal of respiratory
influences on systolic pressures and R-R intervals by partialization reduces coherence between the latter signals from close
to 1.0 to ⬍0.5 (1).
I subscribe to the view that blood pressure changes provoke
parallel R-R interval changes—a cause-and-effect baroreflex
relation. However, in this physiology, timing is everything.
Before I accept the view that R-R interval fluctuations at
respiratory frequencies are baroreflex responses, someone
J Appl Physiol • VOL
must explain 1) how an arterial pressure change can, within 0.1
s, speed or slow the appearance of the next P wave; 2) how the
kinetics of sinoatrial nodal responses to acetylcholine are
modulated systematically by body position and breathing frequency; and most difficult of all, 3) how baroreflex R-R
interval responses can occur before the arterial pressure
changes that provoke them. I submit that the last possibility,
that effects can precede causes, turns logic on its head.
REFERENCES
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Fig. 1. Cross-spectral analysis of systolic pressures and R-R
intervals in two studies (7, 20). Data shown in A and B were
recorded during fixed-frequency breathing at progressive angles of passive upright tilt (7). The average phase angle was
⫺53° at the low frequency (A) and did not change significantly
during tilt (P ⫽ 0.48, linear regression). Data shown in C and
D were recorded during fixed-frequency breathing (left) and
conventional mechanical ventilation, both at a frequency of
0.25 Hz (20). Respiratory frequency phase angles averaged
⫺25° during fixed-frequency breathing (D; left) and 49° during
mechanical ventilation (D; right). Neither study reported fixed
phase angles and respiratory frequencies (B and D).
Point:Counterpoint
1742
Dwain L. Eckberg
Medical College of Virginia
Virginia Commonwealth University
Richmond, Virginia
e-mail: [email protected]
J Appl Physiol • VOL
COUNTERPOINT: RESPIRATORY SINUS ARRHYTHMIA IS DUE
TO THE BAROREFLEX MECHANISM
In healthy humans blood pressure and heart periods fluctuate
at respiratory and other frequencies. The extent of these fluctuations is situation and age dependent. Although literature
concurs that most of these fluctuations are reflex driven, some
insist on an exemption for the respiratory oscillations. In view
of the widespread central nervous activity related to respiration, it is reasoned that in the course of evolution the cardiovascular system has, centrally, become entrained to the respiratory drive. This would, teleologically, improve oxygen uptake by increasing heart rate in the inspiratory phase. Here I
make the case that respiratory sinus arrhythmia is mainly a
reflex phenomenon, driven by incoming information from
baroreceptors. I will base this argument on well-established
physiological facts and insight that can be gained from simple
computational models.
This will not refute animal experiments that show respiration
to modulate centrally the blood pressure to heart period reflex.
However, I intend to demonstrate that in awake humans this
phenomenon is insufficient to explain respiration-to-heart rate
relations.
The beauty of modeling is that it puts physiological insight
to the test: does my interpretation of experimental findings
fulfill all the requirements; can it describe what has been
measured; and, still better, does it correctly predict findings
that have not yet been obtained? The problem of modeling is
the complexity of most models: they require so many parameters and mathematical formulas that, to the non-expert reader,
any desired outcome might be obtained. In this essay I will try
to simplify and restrict modeling to the bare minimum; more
complex reasoning and models can be found in the literature.
First, let us look at a picture of common baroreflex physiology (Fig. 1A): baroreflex afferent information is in the brain
stem relayed to cardiac vagal efferent traffic, leading to sinus
node slowing, be it by a full reset of the diastolic depolarization
(5) as depicted, or to a slowing of depolarization (2). In any
case, if this acts sufficiently fast, the next heart beat will be
delayed after a systolic pressure increase, thereby stabilizing
diastolic pressure (Fig. 1C). As has been argued by Dr. Eckberg in his Point preceding this Counterpoint, we may assume
that this can, in humans, occur within one beat, in view of the
latencies involved. Also the founding fathers of the “gold
standard” of baroreflex sensitivity (BRS) measurement came to
this insight in a later publication (6): if resting heart rate in
humans is below ⬃75 beats/min the best correlation between
(increasing) systolic pressures and heart periods is found for
the heart period in which a specific systolic pressure occurs,
rather than for the next heart period. It is strange to see that this
insight did not make it into practice.
Now suppose that in a sequence of beats as depicted in Fig.
1A, suddenly the central nervous system decides to command
an inspiratory movement and at the same time it inhibits
(“gates”) incoming baroreceptor traffic. This would, inevitably,
lead to an increase of the next diastolic pressure, as shown in
Fig. 1B. Rather than dampened diastolic pressure variability at
the respiratory frequency, one would expect conspicuous respiratory blood pressure oscillations.
The jumping between frequency and time domain should be
done with caution. In treating blood pressure and heart period
recordings, it is common practice to reduce the amount of data
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