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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 160 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 161 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. References [1] Barcroft J. Features in the architecture of physiological function. Cambridge: University Press; 1934. [2] Goto K. Pacemaker potential and cardiac nerve impulses evoked by stimuli of the vagus nerve. J Phys Soc Jpn 1979;41:8–9. [3] Noble D. The initiation of the heartbeat. Oxford: Clarendon Press; 1979. [4] Randall WC. Neural regulation of the heart. New York: Oxford University Press; 1977. [5] Katona PG, Paitras JW, Barnett GO, Terry BS. Cardial vagal efferents activity and heart period in the carotid sinus reflex. Am J Physiol 1970;218:1030–7. [6] Levy MN, Martin PJ. Neural control of the heart. In: Bethesda RM. editor. Handbook of Physiology, Section 2. Amer Physiol Soc 1979. p. 581–620. [7] Pokrovskii VM. Alternative view on the mechanism of cardiac rhythmogenesis. Heart Lung Circ 2003;12:18–24. [8] Levy MN, Iano T, Zieske H. Effect of repetitive burst of vagus activity on heart rate. Circ Res 1972;30:186–95. [9] Pokrovskii VM, Shekh-Zade YR. Precisely regulated decrease in the heart rate during vagus irritation. Fisiol Zh SSSR 1980;66:721–5. [10] Reid JV. The cardiac pacemaker: effects of regulatory spaced nervous input. Am Heart J 1969;78:58–64. [11] Zubkov AA. Heart assimilation of vagus stimulation rhythm. Bull Eksp Biol Med 1936;1:73–4. Pokrovskii [12] Pokrovskii VM, Sheikh-Zade YR, Kruchinin MV, Sukach MV, Pokrovsky MV, Urmancheeva TG. Common principles of heart rate control during burst stimulation of vagus nerve in different animals. Fisiol Zh SSSR 1987;73:1325–30. [13] Pokrovskii VM, Sheikh-Zade YR, Kruchinin MV, Urmancheeva TG. Precise control of heart rhythm in primates via burst stimulation of vagus nerve. Bull Eksp Biol Med 1987;104:266–7. [14] Pokrovskii VM, Abushkevich VG, Fedunova LV. Electrophysiological marker of regulated bradycardia. Dokl Akad Nauk 1996;349:418–20. [15] Koepchen HP. Respiratory and cardiovascular ‘‘centers’’: functional entirety or separate structures. In: Schlafke ME, Koephen HP, editors. Central neuron environment. Berlin: Springer-Verlag; 1983. p. 221–37. [16] Pokrovskii VM, Bobrova MA. Spike activity of neurons of the medulla oblongata associated with cardiac and respiratory rhythms. Fiziol Zh Ukraina 1986;32:98–102. [17] Pokrovskii VM, Abushkevich VG, Dashkovsky AI, Shapiro SV. Possibility of heart rhythm control via randomized change in respiratory rate. Dokl Akad Nauk SSSR 1985;283: 738–40. [18] Pokrovskii VM, Abushkevich VG, Dashkovsky AI, Makigonov EA, Shapiro SV, Pokhot’ko AG. Synchronization of myocardial contraction and respiration during thermoregulatory polypnea in the dog. Dokl Akad Nauk SSSR 1986;287:479–81. [19] Pokrovskii VM, Abushkevich VG, Borisova II, et al. Cardiorespiratory synchronization in human. Human Physiol 2002;28:728–31. [20] Pokrovskii VM, Abushkevich VG, Potiagailo EG, Pokhot’ko AG. Cardiorespiratory synchronism: revealing in human, dependence on properties of nervous system and functional conditions of an organism. Usp Fisiol Nauk 2003;34:89–98. [21] Kollai M, Koizumi K. Cardiac vagal and sympathetic nerve responses to baroreceptor stimulation in the dog. Pflugers Arch 1989;413:365–71. [22] Trembuch AB. To the question on the functional importance of the ‘‘cardiac’’ neurons of the medulla oblongata. In: Pokrovskii VM, editor. Neural regulation of the heart activity. Krasnodar: 1981. p. 33–42.