Tomoyuki Yambe,

summary: From now on, the research of an artificial heart will go in an age to investigate QOL. When it thinks about QOL, the problem of the autonomic nerve is important. However, there is a little research of this field very much. Long ago, Atsumi et al studied about the artificial heart syndrome and the autonomic nerve. Kojima and Nose reported about RP (Rotary pump) and hemodynamic fluctuations. Direct record of an autonomic nerve discharges in an animal with an artificial heart had begun in the autonomic nerve activities record of the mechanical heart in the world, and succeeded in Tohoku. The autonomic nervous system function attracts attention all the more in RP as well in the clinical beginning. We give the outline about the recent autonomic nerve research.
Key words: Ventricular assist device, Rotary pump, Autonomic nervous system, Spectral analysis, chaos

Long ago, the survival competition of animals with a total artificial heart was carried out in all over the world. No one thought about an autonomic nerve in the age when they were competing in the survival world record with each other. In this situation, a few researchers paid attention to the autonomic nerve.
Atsumi proposed the general idea of "the artificial heart syndrome" (1). They reported that an autonomic nerve played an important role in this syndrome.
Vasku in Czech paid attention to the autonomic nerve of the atrium of the calves with the total artificial hearts (2). They pursued this study from the pathological findings in the microscope.
Electrical stimulation to the end of the autonomic nerve in the atrium left after the TAH implantation was reported by Imachi (1).
An interesting fluctuation in an animal with rotary blood pump animals with total nonpulsatile flow was reported from Nose in Cleveland Clinic. They reported some interesting fluctuation in the chronic non pulse animals.
The autonomic nerve activities of the animals with artificial heart and assist device were recorded in Tohoku University in the world for the first time (4-6). It may be useful if we want to evaluate the autonomic function directly. They recorded the renal sympathetic nerve activity (RSNA) in animals with artificial hearts.
After that, various investigators record an autonomic nerve activity. RSNA was recorded in circulation with artificial devices in the National Cardiovascular Center (NCVC) and Kyushu University (7,8).
Institute of Development, Aging and Cancer (IDAC), in Tohoku University proposed an artificial heart control algorithm by the use of a tonus of the sympathetic nerve in the world first.
Mabuchi et al. reported autonomic nerve control for an artificial heart in the same way with us (9, 10). Their concept of the control algorithm for an artificial heart was already proposed by Tohoku University in 1994 (9,10). Most ideal artificial heart control may be achieved by the use of an autonomic nerve information including sympathetic nerve discharges as we shown before and Mabuchi's following report, because natural heart was controlled by an autonomic nervous system.
Furthermore, we paid attention to the analysis by the fluctuations in the waking condition, recently.


A lot of investigators noted that the Fluctuations in hemodynamic parameters gave us a lot of information concerning the cardiovascular regulatory system (11-15). Until now, various researchers investigated the fluctuations in the hemodynamics, however, a few investigators studied the fluctuation in hemodynamic waveform in artificial heart circulation.
It was well known that the development of recent non-linear mathematics theory brings great contribution to a field of medicine and biology 16-23). Among all these general ideas, the Deterministic chaos and fractal structure are the important keys, which can analyze the "complex system". Mandelbrot invented the word called "fractal" newly in 1982 (16-20). Fractal represents the self similarity that doesn't depend on a scale. This character is recognized in the structure as branches of a tree. In the anatomical consideration, there are many examples of fractal structure as a blood vessel or respiratory tract. And fractal structure on time is important. In an economical mathematics, the Curves of stocks are the famous examples. A lot of applications are applied in the various fields. In a field of medicine, an electrocardiogram (ECG) or an electroencephalogram (EEG) is nominated for the examples. Fractal is evaluated quantitatively by a dimension in these applications.
We concluded the recent progress of the research activity concerning the autonomic nervous system and an artificial heart. And our recent data of an autonomic function analysis during assisted circulation was reported and consideration was added to these data.

Analysis of the fluctuation
Animal experiments were performed to evaluate the autonomic nerve function. After the anesthesia were induced with halothane inhalation in the adult goats, the left pleural cavity were opened through the fourth intercostal space under mechanical ventilation. Electrodes for electrocardiogram were put on, and arterial blood pressure (BP), left atrial pressure (LAP) were monitored continuously with catheters inserted into the artery and left atrium through the left femoral artery and left atrial appendage, respectively. For the left assist heart implantation, a polyvinyl chloride (PVC) cannulae was inserted in the left atrium and descending aorta, and it was fixed with ligation. In this experiment, totally implantable VAD named Vibrating flow pump (VFP) was used. VFP were made with oscillating central tube, only one Jelly-fish valve mounted at the outside of the central tube, and surrounding four coils and four permanent magnets to shake the vibrating tube back and forth electromagnetically. Blood always washed out the outside chamber of this VFP to prevent thrombus formation. After the chest were closed, the goats were placed in the cage and extubated after waking. The hemodynamic derivatives were recorded to data recorder. The data was input to personal computer through A-D convertor. Integration, statistics handling, frequency analysis, non-linear analysis was carried out.
Fast fourier transform (FFT) was carried out for the purpose of frequency analysis of data converted into to heartbeat unit. Mayer wave peak and respiratory peak was clearly shown in the spectrum and the plotting was performed into 2 dimensions return map, and fractal dimension was calculated. Box counting was used in a calculation of a dimension.
It is known that the autonomous nerve gives influence to blood vessel resistance. And heart rate variability was mediated by the autonomic nervous system. So, frequency analysis of heartbeat fluctuation was done. As the results, significant change was recognized in the Mayer wave fluctuation, which was reported that sympathetic nerve system controlled mainly. Alteration of Mayer wave was recognized by the left heart assistance of VFP. Furthermore, from heartbeat fluctuation, fractal dimension was calculated to carry out the analysis that paid attention to the whole system in addition to sympathetic nerve. In this study, a dimension was calculated by the use of Box counting. If we observe an example of calculation course, the result showed that it was according to power law, which was character of fractal and after the conversion into a logarithm, fractal dimension is calculated from slope. Our most important results of the nonlinear data showed that the fractal dimension of heartbeat fluctuation tended to decrease by the left heart assistance of VFP. This alteration of the fractal dimension means a change of non-linear dynamics system to control conditions, suggesting the revolution to simplicity of non-linear dynamics system. Evaluation of the fluctuation showed us an information concerning the cardiovascular regulatory system.

Fluctuation and control

In this paper, we introduce the new basic concept for an automatic control algorithm for TAH using fluctuations in the circulatory system. A lot of famous researchers reported that fluctuation of hemodynamics reflects ongoing information of the autonomic nervous system. For an evaluation of the information of an autonomic nervous system, we paid attention to these components of rhythmical fluctuation in this study.
But unfortunately, we could not measure the HRV in the creatures with an artificial heart, because there was no heart. Accordingly, an only information that could easily measure may be the peripheral vascular resistances, so that, we paid attention to the fluctuations of the vascular resistance, which could measure even during an artificial heart circulation.
Recording time series data of hemodynamic parameters using healthy adult goats in the awake conditions was performed by the use of the chronic animal experiments. Rhythmical fluctuations in the peripheral vascular resistances were calculated in this study. The Probability of an predictive automatic TAH control system using an autonomic nerve information was considered. Arterial blood pressure was monitored continuously with catheters inserted into the aorta through the left internal thoracic artery. Central venous pressure (CVP) was measured by the fluid-filled catheter inserted through the internal thoracic vein. Cardiac out put was measured with an electromagnetic flow meter attached to the ascending Aorta. All hemodynamic time series data were monitored continuously during the experiments (Fukuda Denshi: MCS-5000) recorded in the awake condition.
Real time monitoring of the peripheral vascular resistances was embodied by this measurement. Band pass filter was established to 0.04 - 0.15 Hz, which was reported to be the Mayer wave fluctuations in hemodynamic time series data. Behavior of the time series data suggesting that band passed data gave us an information different from peripheral vascular resistances. Rhythmical fluctuations suggesting vasomotion was observed in the time series.
If we consider the automatic control algorithm, an important problem of the predictive control for TAH using neural information was the time lag of the prediction. In this study, we calculated the cross correlation function of the band pass value of the peripheral vascular resistances and cardiac output.
When we observed the cross correlation of the band-passed peripheral vascular resistances and the cardiac output, significant peak was observed in the almost five seconds after, suggesting the possibility to predict the cardiac output from the autonomic information.
By the use of this information, we predicted the cardiac out put in future by the use of the Mayer wave in the peripheral vascular resistances, which could easily, obtained from the creatures with an artificial heart. X axis showed a band passed peripheral vascular resistances and Y-axis showed measured cardiac out put recorded five seconds after. Significant correlation was observed in the figure, suggesting the probability of the realization of the predictive automatic control for an artificial heart system.
For the QOL of the patient with an artificial heart, information from biological system may be important, because artificial heart must be respond to the physical activity. Pump out put of an artificial heart must increase, when runs. And output must decrease, when sleeps. To control an artificial heart, biological information may be necessary. However, it is very difficult to detect autonomic nerve activity directly in the chronic stage. In this study, stable measurement of an autonomic nerve information was realized by the use of the hemodynamic fluctuations. It may become insensitive compared with the direct measurement as we shown before, we selected the stability.
In this study, time series curve of the Mayer wave of vascular resistance was provided. This index was reported to be very useful for the parameter of the sympathetic nervous system. It was compared with time series curve of cardiac output. After a change of Mayer wave, increase in the cardiac output was observed after five seconds. This phenomenon may be interpreted that sympathetic nerve control the changes of the cardiac output. These results suggest that artificial heart may be controlled by the@measurement of the Mayer wave of the vascular resistance.
Of course, development of another control algorithm for an@artificial heart by the use of direct measurement has been still ongoing in Tohoku University.
Recently we measured the vagal nerve activity in the chronic animal experiments in the awake condition.
It may give us a useful information to control an artificial heart in future.

The mathematical methodology of this paper was discussed in the workshop "Various approaches to the complex systems" held at the International Institute for Advanced Studies.
The authors thank Mr. Kimio Kikuchi for experimental preparation and kind cooperation, Miss Mika Katana,, and Mrs. Hisako Iijima for their excellent technical assistance and kind cooperation.
This work was partly supported by a Grant-in-aid for Scientific Research (114580253), Research Grant for Cardiovascular Diseases from the Ministry of Health and Welfare and Program for Promotion of Fundamental Studies in Health Science of Organizing for Drug ADR Relief, R&D Promotion and Product Review of Japan.


1. Atsumi K:@The coming ERA of Biomation Technology. NIP press, 1989, Tokyo, Japan.
2. Vasku J: Total artificial heart research in Czechoslovakia. Artificial Heart 1, ed by T.Akutsu, Springer-Verlag, Tokyo, Japan. pp161-180, 1986.
3. Kojima R, Nose Y: Rhythmical fluctuation of arterial pressure after implantation of cardiac prosthesis. Artif Organs 1994: 18: 1-6.
4. Yambe T, Nitta S, Sonobe T, Tanaka M, Miura M, Satoh N, Mohri H, Yoshizawa M, Takeda H. Effect of left ventricular assistance on sympathetic tone. Int J Artif Organs 1990;13F681-686
5. Yambe T, Nitta S, Katahira Y, Sonobe T, Naganuma S, Akiho H, Chiba S, Kakinuma Y, Hayashi H, Tanaka M, Miura M, Satoh N, Mohri H, Yoshizawa M, Takeda H. Postganglionic sympathetic nerve activity with correlation to heart rhythm during left ventricular assistance. Artif Organs 1991; 15: 212-217.
6. Yambe T, Nitta S, Katahira Y, Sonobe T, Naganuma S, Kakinuma Y, Matsuzawa H, Tanaka M, Miura M, Sato N, Mohri H, Takeda H, Yoshizawa M. Fundamental rhythm of sympathetic nerve discharges in animals with total artificial hearts. ASAIO J 1992; 38: 91-95.
7. Toda K, Tastumi E, Taenaka Y, Masuzawa T, Miyazaki K, Nakatani T, Baba Y, Eya K, Wakisaka Y, Takano H. Influence of ventricular fibrillation on sympathetic nerve activity under biventricular bypass circulation. Artif Organs 1995; 20: 143-146.
8. Tokunaga S, Fukae K, Hisahara M, Miyamoto K, Nishida Y, Tanoue Y, Ochiai Y, Tominaga R, Yasui H. Effects of Hypothermia during cardiopulmonary bypass and circulatory arrest on sympathetic nerve activity in rabbits. JJME 1994; 32(suppl); 84.
9. Yambe T, Nitta S, Chiba S, Saijoh S, Naganuma S, Akiho H, Hayashi H, Tanaka M, Miura M, Satoh N, Mohri H, Yoshizawa M, and Takeda H: Estimation of the following cardiac output using sympathetic tone and hemodynamics for the control of total artificial heart. Int J Artif Organs 15: 606-610, 1992.
10. Mabuchi K, Kunimoo M, Kanbara H, Genno H, Chinzei T, Matuura H, Suzuki T, Tago T, Abe Y, Imachi K, Fujimasa I: Attempt to use sympathetic nerve signals for the control of an artofocoal heart system Int J Artif Organs 1996; 527: 19 (abstract)
11. Denton TA, Diamond GA, Helfant RH, Khan S, Karaguenzian H: Fascinating rhythm - a primer to chaos theory and its application on cardiology. Am Heart J 20: 1419-1440, 1990.
12. Yambe T, Nitta S, Sonobe T, Naganuma S, Kakinuma Y, Izutsu K, Akiho H, Kobayashi S, Ohsawa N, Nanka S, Tanaka M, Fukuju T, Miura M, Uchida N, Sato N, Tabayashi K, Koide S, Abe K, Takeda H, Yoshizawa M: Deterministic chaos in the hemodynamics of an artificial heart. ASAIO J 41: 84-88, 1995.
13. Tsuda I, Tahara T, Iwanaga H: Chaotic pulsation in human capillary vessels and its dependence on mental and physical conditions. Int J Bifurc Chaos 2: 313-324, 1992.
14. Yambe T, Nitta S, Sonobe T, Naganuma S, Kakinuma Y, Kobayashi S,Tanaka M, Fukuju T, Miura M, Sato N, Mohri H, Koide S, Takeda H, YoshizawaM, Kasai T, Hashimoto H: Chaotic hemodynamics during oscillated blood flow.Artif Organs 18: 633-637, 1994.
15. Yambe T, Nitta S, Sonobe T, Naganuma S, Kakinuma Y, Kobayashi S, Nanka S, Ohsawa N, Akiho H, Tanaka M, Fukuju T, Miura M, Uchida N, Sato N, Mohri H, Koide S, Yoshizawa M, Abe K, Takeda H: Chaotic behavior of the hemodynamics with ventricular assist device. Int J Artif Organs 18: 17-21,1995.
16. Mandelbrot BB.The Fractal Geometry of the Nature. Freeman, San Francisco, 1982
17. Yambe T, Nanka S, Naganuma S, Kobayashi S, Akiho H, Kakinuma Y, Ohsawa N, Nitta S, Fukuju T, Miura M, Uchida N, Tabayashi K, Tanaka A, akeda H, Yoshizawa M. Can the artificial heart make the circulation become fractal ? Int J Artif Organs 1995; 18: 190-196.
18. Crutchfield JP, Farmer JD, Packard NH, Shaw RS . Chaos. Sci Am 1986;255: 46-5723.
19. Yambe T, Nanka S, Nitta S, Iwase S, Sugiyama Y, Mano T. Fractal dimension analysis of the muscle sympathetic nerve activity. Pathophysiology 1995; 22: 173-176.
20. Goldberger AL, Rigney DR, West BJ (1990) Chaos and fractals in human physiology. Sci Am 1990; 259: 35-41
21. West BJ. Fractal physiology and chaos in medicine. World Scientific, Singapore, 1990
22. Yambe T, Nanka S, Naganuma S, Kobayashi S, Nitta S, Fukuju T, Miura M, Uchida N, Tabayashi K, Tanaka A, Yoshizumi N, Abe K, Takayasu H,Yoshizawa M, Takeda H. Extracting 1/f fluctuation from the arterial blood pressure of an artificial heart. Artif Organs:(in press)
23. Kobayashi M, Musha T. 1/F fluctuation of heart rate period. IEEEtrans Biomed Eng 1982; 29: 456-7.