Download Hierarchy of the heart rhythmogenesis levels is a

Medical Hypotheses (2006) 66, 158–164
http://intl.elsevierhealth.com/journals/mehy
Hierarchy of the heart rhythmogenesis levels
is a factor in increasing the reliability of
cardiac activity
Vladimir M Pokrovskii
*
Kuban State Medical University, Department of Normal Physiology, Sedin Street, 4,
Krasnodar 350063, Russia
Received 3 June 2005; accepted 27 June 2005
Summary Along with the existence of an intracardiac pacemaker a generator of cardiac rhythm exists in the central
nervous system – in the efferent structures of the cardiovascular center of the medullar oblongata. Neural signals
originating there in the form of bursts of impulses conduct to the heart along the vagus nerves and after interaction with
cardiac pacemaker structures cause generation of the cardiac pulse in exact accordance with the frequency of the neural
bursts. That the intrinsic cardiac rhythm generator is a life-sustaining factor that maintains the heart pumping function
when the central nervous system is in a stage of deep inhibition. The brain generator is the factor that provides the heart
with adaptive reactions to changes in the environment. The hierarchy of the two duplicating levels of rhythmogenesis
provides reliability and functional perfection of the cardiac rhythm generation system in the whole organism.
c 2005 Elsevier Ltd. All rights reserved.
In intact humans and animals the heart rhythm is
formed in the cardiovascular center of the medulla
oblongata, neural signals travel to the heart from
the brain along the vagus nerves and interact with
cardiac pacemaker structures, causing excitatory
gerneration in exact accordance with the frequency of the signals, coming from the brain.
Introduction
* Tel./fax: +7 861 268 55 02.
E-mail address: [email protected].
Noting that high reliability of functioning is based
on duplication of functions J. Barcroft wrote in
1934: ‘‘So frequent indeed is duplication that it
can scarcely be accidental; it seems to be a
definite feature in the architecture of function,
the more impressive because it is achieved in such
different ways – but I have often been surprised
that the heart itself was not duplicated. It is always
surprising to me that there is only one heart!’’ [1].
The generally accepted understanding about the
mechanisms of cardiac rhythm generation consists
of the following simplified ideas. The cardiac rhythm
arises in the specialized structures of the heart,
which have pacemaker properties. The autonomic
nervous system exerts a secondary, remedial effect
on the intracardiac rhythm generator. In particular,
0306-9877/$ - see front matter c 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2005.06.028
Hierarchy of the heart rhythmogenesis levels is a factor in increasing the reliability of cardiac activity
the sympathetic nerves accelerate the heart rate,
while the parasympathetic ones decelerate it. This
understanding we supported by multiple experiments with cutting and subsequent electrical stimulation of the extracardiac (parasympathetic and
sympathetic) nerves. It has been established that
rhythmic modulation was dependent on the speeding up of the spontaneous depolarization of the
pacemaker cells during stimulation of sympathetic
nerves and on slowing down of depolarization during
parasympathetic activation [2–4]. However, such
mechanism of rhythmogenesis, while providing sufficient reliability of the cardiac rhythm generation,
cannot provide the whole spectrum of cardiac adaptive reactions in the whole organism. Recently
obtained data allows reevaluating critically the current understandings about the mechanisms of heart
rhythm generation.
In particular, a classical phenomenon observed
when stimulating the peripheral end of the cut
vagus nerve, resulting in deceleration of the heart
rate (or even cardiac arrest), cannot be an adequate model for understanding the processes of
heart rhythm neural regulation. First, an abrupt
inhibition of heart activity is not observed in the
process of natural regulation. Indeed, all efferent
fibers of the vagus nerve never get excited simultaneously in natural conditions, as it happens under
artificial suprathreshold electrical stimulation of
the nerve. Moreover, the experimental nerve stimulation usually consists of a continuous train of impulses, whereas in natural conditions nerve
impulses are grouped in ‘‘volleys’’ (‘‘bursts’’) synchronized with heart beats [5,6].
Newly obtained data allowed us to formulate nonstandard ideas about the mechanisms of cardiac
rhythm generation. We have concluded that along
with the existence of an intracardiac generator of
cardiac rhythm, a separate generator exists in the
central nervous system, in the efferent structures
of the cardiovascular center in medulla oblongata.
Nervous signals, originating there in form of bursts
of impulses, travel to the heart along the vagi and
interact with cardiac pacemaker structures, causing
excitatory generation in exact accordance with the
frequency of the bursts [7]. This process is accompanied by characteristic electrophysiological changes
in the intracardiac pacemaker.
Experimental data and analysis
The protocol and procedures employed were
reviewed and approved by the Bioethics Committee of the Krasnodar Education and Science
Department.
159
The experimental findings leading to the formulation of the above hypotheses may be divided into
two groups. The first group consists of data obtained during electrical stimulation of the peripheral end of the cut cervical vagus with repetitive
bursts of impulses. The second group is represented by data demonstrating the ability of the
heart to follow the rhythm of bursts of impulses
formed in the central nervous system.
Reproduction by the heart of the rhythm of
electrical stimuli applied to the vagus
During stimulation of the vagus with bursts of impulses applied with a gradually increasing frequency the heart rate slows. When the increasing
bursts’ frequency and the slowing heart rate become equal, a 1:1 neural-heart synchronization ratio occurs. Now the heart responds to every burst
of vagal impulses by a single contraction, following
a certain delay [8–11]. For each set of burst
parameters (e.g. number of impulses in the individual burst, amplitude, etc.) there is a range of frequencies within which the heart rate follows
precisely the rhythmicity imposed by the vagus
nerve stimulation (Fig. 1).
As seen from the Fig. 1 adjacent ranges partially
overlap, and increasing the number of vagal impulses in a burst permits synchronization at progressively slower heart rates in the range from
132 to 66 bpm. We studied this phenomenon in different species (monkey, cat, rabbit, dog, rat, guinea pig, coypu, pigeon, duck, and frog). It has
been observed in all tested animals and this similarity supports its general biological significance
[12,13]. These facts demonstrate the existence of
a robust general biological phenomenon whereas
bursts of impulses conducted to the sinoatrial node
via the vagus nerve cause the heart rhythm to follow the rhythm of the bursts.
Electrophysiological mechanisms underlying
this cardiac rhythm control have been elucidated
in experiments with a computer mapping of the
sinoatrial node region. Bioelectric activity has
been simultaneously recorded from 64 points,
and isochronous maps of origin and spread of
excitation in the sinoatrial node region have been
analyzed. We established that in control, and also
during bradycardia caused by traditional (continuous) stimulation of the vagus nerve, the area of
early depolarization constituted a single focus.
However, when the heart was forced to follow
the frequency of the repetitive vagal burst stimulation, the area of early depolarization became
wider and included not 1 but 2–11 of the mapped
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Pokrovskii
nals coming via the electrically stimulated vagi
[14].
Reproduction by the heart of the rhythm of
signals generated in the central nervous
system
Figure 1 Synchronization of heart rate and vagus nerve
rhythm during electrical nerve stimulation. Horizontal
axis – quantity of impulses in the burst. Vertical axis –
heart rate in beats per minute, equal to the bursts’
frequency. x – baseline spontaneous heart rate
(172.9 ± 5.8 bpm). Vertical line segments: rate range
within which acceleration or deceleration of the bursts
of vagal impulses was associated with heart rate
synchronization.
points (Fig. 2). Thus, a pronounced widening of
the area of early depolarization in the sinoatrial
node appeared to be an electrophysiological marker of obeying by the heart to the rhythm of sig-
There is a well-known connection between brain
structures responsible for respiratory and heart
rhythmogenesis. The uniformity of the underlying
mechanisms is so considerable that these structures have been considered functional entirety
rather than separate entities [15]. We used this
characteristic feature to create a model for study
the formation of the cardiac rhythm in an organism
by means of signals, generated in the central nervous system (medulla oblongata) and passed to
the heart via vagus nerves.
It has been shown in our investigations that
same medullar interneuron in efferent nuclei of
the vagus can produce an impulse activity sometimes corresponding to the breathing rhythm,
and sometimes to the heart contraction rhythm.
During inhalation the interneuron’s activity is synchronized with diaphragm contraction, and during
exhalation it is synchronized with heart contractions [16]. Usually both human and animal breathe
less often than the heart contracts. At the same
time respiration, among all other autonomic functions, possesses a unique feature – the ability of
voluntary control. In order to achieve the predetermined level of heart rate acceleration, we
asked volunteers to breath in synchrony with
photo-stimulator’s light bulb, the frequency of
which was set to exceed the initial heartbeat frequency by 5–10%. After a transitional period of
Figure 2 Isochronous maps of depolarization origin and spread in the sinoatrial node in the acute experiment in a cat.
(1) Baseline conditions. (2) During synchronization of vagal and cardiac rhythms. (3) After cutting vagus nerves. The
black colour shows the position of the early depolarization area. CRISTA, crista terminalis; NSA, sinoatrial node area;
VCI, vena cava inferior; VCS, vena cava superior.
Hierarchy of the heart rhythmogenesis levels is a factor in increasing the reliability of cardiac activity
20–30 cardiac cycles, the cardiac and respiratory
rhythms synchronized [17]. The heart contraction
frequency was controlled in this fashion in a range
of 10–20 bpm. Cardiorespiratory synchronization
was determined on polygraph recording by equality of the intervals: (1) between photostimulator
marks, (2) between the R waves of ECG (R–R
interval) and (3) between identical pneumogram
elements (Fig. 3). We revealed that cardiorespiratory synchronization can be detected in all somatically healthy subjects. The limits and width of
the synchronization ranges for different age
groups are presented in Fig. 4.
Further analysis of the mechanisms of synchronization of cardiac and respiratory activity was performed in experiments in dogs. Since animals
cannot voluntarily speed up the breathing, we used
overheating to induce hurried breathing (tachypnea). For that purpose, animals were placed in a
thermo-camera at 38 °C. After 1.0–1.5 h the
breathing frequency reached the heartbeat frequency and soon breathing and heartbeat rhythms
synchronized at a rate of about 180 per minute.
Later on during the test, the breathing frequency
could increase or decrease leading to synchronous
changes of the heartbeat frequency. The range of
respiratory and cardiac frequencies synchronization was up to 50 bpm. However, the synchronism
disappeared when the vagus nerves were cut. A
similar effect we observed when the animal was injected with atropine, which interrupts the transmission of excitation from the vagal endings to
the heart. Thus the heartbeats synchronous with
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breathing were results of signals coming to the
heart by vagus nerves [18].
The experiments in animals [18] and the observations in humans [19,20] have shown that at high
frequency of excitation of the respiratory center,
the cardiac efferent neurons in the medulla oblongata get entrained in this rhythmicity. The signals
initially formed as bursts of impulses come to the
heart via the vagus nerves and by interacting with
the intracardiac pacemaker structures cause excitation in exact accordance with the frequency of
the bursts.
It should be stressed that the above-discussed
models of cardiac and respiratory rhythm synchronization are only an experimental way of demonstrating a potential ability of cardiac rhythm
formation by means of discrete signals generated
in the center, and coming to the heart via the vagi.
In normal conditions cardiac medullary centers
might have their own periodicity. For example, it
is known that vagal bursts of impulses synchronous
with the cardiac rhythm could be caused by baroreceptor feedback [21]. However, as demonstrated in
our laboratory [22], even after complete deafferentation one could observe generation of signals
in the vagus center of medulla oblongata with the
rhythm of the heart contractions. For this purpose
the author induced cardiac arrest by intracoronary
administration of KCL. The activity of the neurons
in the efferent nucleus of the vagus in medulla
oblongata continued for some time in the rhythm
of the beating heart before its arrest. In this case
the afferent signaling was stopped, suggesting that
what we observed was the intrinsic automatism of
the medulla oblongata heart center.
Electrophysiological processes in the
sinoatrial node when the heart reproduces
the signals coming via vagus nerve
Figure 3 Ascertaining of the fact of the cardiorespiratory synchronism presence (scheme): (1) photostimulator
lamp flashes mark, (2) electrocardiogram, (3) pneumogram. Vertical lines shows the principle of ascertaining of
heart and respiratory rhythm synchronization fact.
Further investigations were performed on the basis
of synthesis of the two groups of above-mentioned
facts: first, the pronounced widening of early depolarization area in the sinoatrial node during
entrainment of the heart rhythm by the rhythm
of signals coming to the heart via the vagus nerve,
and second, the reproduction by the heart of the
rhythm of signals arising in the efferent structures
of the medulla oblongata and coming to the heart
via the vagi (cardio-respiratory synchronism revealed in humans and animals).
We have studied in chronic dogs the spread of
excitation in the sinoatrial node during synchronization of the brain and heart events. Mapping of
the sinoatrial node area during the surgical stage
162
Pokrovskii
Figure 4 Cardiorespiratory synchronism parameters according to the age groups. (a) Males parameters. (b) Females
parameters. Y-d – heart rate per min. X-d – age groups. Shading part – cardiorespiratory synchronism range width.
–r– baseline heart rate, –j– cardiorespiratory synchronism minimum limit, –m– cardiorespiratory synchronism
maximum limit.
of the experiment (under anesthesia) revealed an
early depolarization area in the sinoatrial node
that was represented by a single focus. After recovery from anesthesia and during post-operative
activities (interacting with personnel, eating, etc)
the early depolarization area widened. Taking
into consideration our previous observations we
hypothesized that this might represent switching
on-and-off of the central pacemaker rhythm. Atropinization of the animals or cutting of the vagus
nerves resulted in reduction of the wider early
depolarization region to one focal point again.
The fact that the pronounced reduction of the
early depolarization area in the sinoatrial node in
these animals was correlated with the ceasing of
signals in the vagus nerves we also demonstrated
in the case of cardio-respiratory synchronism
caused by thermotachypnea. When synchronism
was achieved, the early depolarization area in the
sinoatrial node was abruptly increased, but when
the vagus nerves were cut (or atropine was administered) it was reduced to one point.
The mapping of the sinoatrial node region in
the setting of central driving rhythm in human
fully reproduced the phenomena that we obtained
in the chronic experiments in dogs. Fig. 5 represents sinoatrial node region mapping which we
did in order to reveal reestablishment of the central driving rhythm in patient undergoing cardiac
surgery. The mapping immediately after the oper-
Hierarchy of the heart rhythmogenesis levels is a factor in increasing the reliability of cardiac activity
163
Figure 5 Dynamics of the zone of initiation of the excitement in the sinoatrial node in human (explanations are given
in the text). On the scheme: AD, auriculum dexter; VCI, vena cava inferior; VCS, vena cava superior; VD, ventriculum
dexter.
ation revealed the early depolarization region to
be limited to a single focus (panel a). One day later the early depolarization region covered an
area between 2 electrodes (panel b), two days
later in the morning – 3 electrodes (panel c), in
the afternoon – 5 electrodes (panel d), and in
the evening – 6 electrodes (panel e). This demonstrated the switching-on of the central driving
rhythm. The described dynamics of the early
depolarization region correlated with an improvement in patient’s common feeling and reestablishment of ability to elicit cardiorespiratory
synchronism during breathing in time with the
blinking of the photo-stimulator’s lamp.
Another intriguing observation is related to the
dynamics of the cardiac R–R intervals. It has
been noted that, both in animals and humans,
essentially stable R–R intervals (i.e., very low
heart rate variability) accompanied the presence
of intracardiac pacemaking as confirmed by mapping of a single-point depolarization in the sinus
node region. In contrast, in the setting of central
driving rhythm there is an increase in both the
area of sinus node depolarization, and the degree
of heart rate variability. This suggests a possible
causality that might provide better mechanistic
understanding for the dynamic changes in the
heart rhythm.
Conclusion
Taken together the facts presented here demonstrate the existence of a rhythm generator in the
central nervous system along with the cardiac
rhythm generator in the heart itself. The intracardiac generator is a life-sustaining factor that assures
the pump function of the heart when the central
nervous system is in a stage of deep inhibition. The
central generator supports the heart’s adaptive
reactions in normal conditions. The heart’s ability
to reproduce the central rhythm is based on the
specificity of electrophysiological processes in the
intracardiac pacemaker. The hierarchy of the two
duplicating levels of rhythmogenesis provides reliability and functional perfection of the cardiac
rhythm generation system in the whole organism.
164
The offered novel hypothesis is likely to stimulate
further endeavors leading to: (1) elucidation of the
origin of heart adaptive reactions, (2) understanding
the mechanisms of heart rhythm disturbances and
the ways for their correction, (3) discovering the
physiological basis for the components of the heart
rate variability and the practical application of this
utility.
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