DEPARTMENT OF CARDIOVASCULAR MEDICINE KYUSHU UNIVERSITY GRADUATE SCHOOL OF MEDICAL SCIENCES

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Research Units

Bionic Medicine Research Unit

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menu Research Outline Main Research Themes and Relevant Publications Principle Investigator of the group Staff and Research Focus

Main Research Themes and Relevant Publications


  1. Transneural treatment of cardiovascular disease
  2. Elaborate numerical models of biological systems: digital medicine
  3. Ultimate medicine: automated diagnosis and treatment

1. Transneural Treatment of Cardiovascular Diseases

Several fundamental technologies are necessary for the effective development of bionic cardiology. First, if we can decipher the message from the brain stem via the autonomic nerves (listen to the brain), that will pave the way for the body to directly control artificial organs or devices. Next, if we can electronically reconstruct the cardiovascular regulatory function of the brain stem (create the brain) in patients who have lost brain stem function because of diseases, then the body will be able to maintain normal circulation. Further, in the case that the cardiovascular regulatory system malfunctions resulting in illogical control, if we can construct a mechanism that is able to replace the native neural function (overtake the brain) and directly regulates circulation, then we can open the road to rational regulation in disease condition. We shall briefly describe the advanced medicine that listens to the brain, creates the brain and overtakes the brain.

Systematic development of fundamental technology to decipher message from the brain (listen to the brain)
脳を聴く:神経制御のペースメーカー

All organs and tissues of the body are under integrated control by the regulatory system, and each organ or tissue exhibits functions in mutual coherence with each other to maintain vital activities. In recent years, the development of artificial organs such as artificial heart and left ventricular assist pump has progressed at a fast pace. In the present forms, the functions of these artificial organs are regulated independent of other organs in the body. As a result, they do not necessarily function in harmony with the body. However if these artificial organs can be regulated directly by the autonomic nerves, even artificial organs will function as if they were a part of the body.  

The figure below shows the translation of cardiac sympathetic nerve activity using “listen to the brain” technology. The graphs show the relationship between the cardiac sympathetic nerve activity (CSNA) and the heart rate (HR) in rabbits. As shown on the left panels, if we plot the values of the two parameters at a given point in time (instantaneous value), there is no correlation between the two parameters. These data imply that instantaneous heart rate is not determined by the instantaneous nervous activity. One hypothesis is that the heart rate at a point in time (n) reflects not only the magnitude of the nervous activity at time n but also that of the past nervous activity. If so, then past nervous activity can be quantitated using a unique weighted function. h(t)


履歴を考慮したアルゴリズムによる翻訳

This can be expressed as: HR(n)=h(0)NA(n)+h(1)NA(n-1)+. . . .

Using this framework, heart rate can be predicted accurately from the sympathetic nerve activity, as shown in the right panels. A bionic pacemaker with such function will be able to simulate physiological control of heart rate, and will increase the heart rate during exercise stress or emotional stress (such as anger, amazement and excitement) in the same way as a normal heart does. In theory, we have entered an era in which it is possible to develop a system with functions far superior to the existing rate-adaptive pacemaker.

Development of fundamental technology to reconstruct lost brainstem functions (create the brain)
脳を造る:バイオニックブレインによる血液制御

The circulatory system is under strict control of the vasomotor center located in the brainstem. The control of blood pressure is especially well studied, and the arterial baroreceptor reflex is well known. Under normal conditions, this mechanism strongly prevents a change of blood pressure accompanying the movement of blood during a change in posture. The baroreceptor reflex uses a negative feedback system to stabilize blood pressure. As shown in the left panel of the figure, baroreceptors (pressure sensors) localized in the carotid sinus and aortic arch sense a change in blood pressure. This information is transmitted via the afferent fibers to the vasomotor center in the brainstem. The vasomotor center assesses the magnitude of the blood pressure. If the blood pressure is low, commands are sent to the heart to increase heart beat and increase contractility, to the artery to contract blood vessels, and to the vein to contract the vein. As a result, the heart rate, heart contractility, vascular resistance and preload are all increased, and consequently blood pressure increases. The increased blood pressure is again sensed by the baroreceptors and a negative feedback then stabilizes the blood pressure.


In patients with some neural degenerative diseases, the vasomotor center in the brain stem stops to function. These patients suffer from severe orthostatic hypotension due to regulatory failure, even though their blood vessels and heart are normal. Currently there is no effective treatment for these diseases. The right panel of the figure shows the framework of a bionic blood pressure control system that electronically reconstructs the function of the brain stem, aiming at overcoming the pathological condition. Blood pressure is sensed by semiconductor sensors implanted in the artery. The magnitude of the blood pressure is assessed by the bionic brain. Corresponding to the assessed result, the bionic brain then stimulates the efferent pathway of sympathetic nerves and regulates blood pressure to an appropriate level. Therefore, theoretically we have here a pressure control system with the same function as the native vasomotor center. However, the problem is how to transplant the logic of the brainstem to the bionic brain. Experimentally, it is possible to measure the magnitude of change in arterial pressure when a pressure difference is exerted on the baroreceptors. It is also possible to measure the blood pressure response when the  sympathetic ganglion is stimulated. From these data, we can determine the transfer function that converts the desirable blood pressure to nerve stimulation signals in the brainstem.

 
人口脳による血圧制御

This figure shows the performance of an actual bionic brainstem developed based on the theories above. Here, a rat model is used and the celiac plexus is stimulated. When the brainstem function is normal, the decrease in blood pressure is controlled at around 10 mmHg when the mouse is tilted head up from a horizontal upright position. When the brainstem function is lost, the same head-up tilt decreases blood pressure by around 50 mmHg within 2 to 3 sec. However when the bionic system is activated, the blood pressure is maintained at a level approaching that of normal condition.


This series of research on bionic blood pressure control has finally led to clinical application. Utilizing these results, great success in stabilizing blood pressure during surgery has been reported. Although blood pressure dysregulation due to central degenerative disease is rare, this novel treatment strategy is expected to have great potential in the future for the management of orthostatic hypotension, neurally mediated cardiac syncope and blood pressure dysregulation in patients with spinal cord injury.

Development of fundamental technology of bionic brain that overtakes the brain function to achieve cardiac regulation

According to recent studies, the prognosis of heart failure is worsened by inappropriate function of the body regulatory system. Therefore drugs such as beta blockers that have a suppressive effect on the heart or blood vessels have been selected as the first line treatment for heart failure. Certainly, cardiac or vascular suppression can be achieved by methods other than drugs. If we can develop a bionic brain that replaces the vasomotor center and electronically regulates the tension of the sympathetic nerves and vagus nerves which control the heart, this equipment may become a potent treatment for heart failure. To test this possibility, we designed a bionic brain based on the above framework and conducted trial treatment in a rat chronic heart failure model.

To monitor the conditions of the heart, the rat is implanted with a miniature hemodynamic measuring device that transmits wireless signals to an external control device (bionic brain). The bionic brain decides appropriate regulatory conditions, and transmits wireless signals to an autonomic nerve stimulator implanted in the heart of the rat. The implanted stimulator obeys the command signals and regulates the autonomic nerve of the heart (vagus nerve in the right cervical region). Using this system, the heart is controlled by the external bionic brain instead of the brainstem.



不全心に優しい制御

At the beginning of the experiment, myocardial infarction is produced experimentally in the rats to induce serious heart failure. A group of rats controlled by their own brainstem is compared with a group of rats controlled by the bionic brain from 2 weeks after myocardial infarction. As shown in the figure, the mortality rate at 20 weeks is dramatically reduced (p = .008) from 50% (no stimulation, n = 30) to 10% (vagal stimulation, n = 22) by treatment with the bionic brain. The reasons for the marked effectiveness of the bionic treatment strategy have not been fully elucidated. Decreased pulse rate, improved energy metabolism and anti-inflammatory effect are some of the possible effects that improve survival, but research is being continued to elucidate the mechanisms. Development of devices to be implanted with implantable cardioverter defibrillator (ICD) or cardiac desynchronisation therapy (CRT) device is also ongoing.

Relevant publications
  1. Zheng C, Kawada T, Li M, Sato T, Sunagawa K, Sugimachi M. Reversible vagal blockade in conscious rats using a targeted delivery device. J Neurosci Methods. 2006;156(1-2):71-5.
  2. Yanagiya Y, Sato T, Kawada T, Inagaki M, Tatewaki T, Zheng C, Kamiya A, Takaki H, Sugimachi M, Sunagawa K. Bionic epidural stimulation restores arterial pressure regulation during orthostasis. J Appl Physiol. 2004; 97: 984-90. 
  3. Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats.  Circulation. 2004; 109: 120-4.
  4. Sato T, Kawada T, Inagaki M, Shishido T, Sugimachi M, Sunagawa K. Dynamics of sympathetic baroreflex control of arterial pressure in rats. Am J Physiol Regul Integr Comp Physiol. 2003;285(1):R262-70.
  5. Sato T, Kawada T, Sugimachi M, Sunagawa K. Bionic technology revitalizes native baroreflex function in rats with baroreflex failure. Circulation. 2002; 106: 730-4.
  6. Sunagawa K, Sato T, Kawada T. Integrative sympathetic baroreflex regulation of arterial pressure. Ann N Y Acad Sci. 2001;940:314-23.
  7. Kawada T, Chen SL, Inagaki M, Shishido T, Sato T, Tatewaki T, Sugimachi M, Sunagawa K. Dynamic sympathetic control of atrioventricular conduction time and heart period. Am J Physiol Heart Circ Physiol. 2001;280(4):H1602-7.
  8. Kawada T, Sato T, Shishido T, Sugimachi M, Sunagawa K. Closed-loop estimation of the open-loop carotid sinus baroreflex transfer function for the use of animal experiments in space. J Gravit Physiol. 2000;7(2):P137-8.
  9. Kawada T, Inagaki M, Takaki H, Sato T, Shishido T, Tatewaki T, Yanagiya Y, Sugimachi M, Sunagawa K. Counteraction of aortic baroreflex to carotid sinus baroreflex in a neck suction model. J Appl Physiol. 2000;89(5):1979-84.
  10. Kawada T, Sato T, Inagaki M, Shishido T, Tatewaki T, Yanagiya Y, Zheng C, Sugimachi M, Sunagawa K. Closed-loop identification of carotid sinus baroreflex transfer characteristics using electrical stimulation. Jpn J Physiol. 2000;50(3):371-80.
  11. Yoshimura R, Sato T, Kawada T, Shishido T, Inagaki M, Miyano H, Nakahara T, Miyashita H, Takaki H, Tatewaki T, Yanagiya Y, Sugimachi M, Sunagawa K. Increased brain angiotensin receptor in rats with chronic high-output heart failure. J Card Fail. 2000 ;6(1):66-72.
  12. Chen SL, Kawada T, Inagaki M, Shishido T, Miyano H, Sato T, Sugimachi M, Takaki H, Sunagawa K. Dynamic counterbalance between direct and indirect vagal controls of atrioventricular conduction in cats. Am J Physiol. 1999;277(6 Pt 2):H2129-35.
  13. Kawada T, Sato T, Shishido T, Inagaki M, Tatewaki T, Yanagiya Y, Sugimachi M, Sunagawa K. Summation of dynamic transfer characteristics of left and right carotid sinus baroreflexes in rabbits. Am J Physiol. 1999;277(3 Pt 2):H857-65.
  14. Sato T, Kawada T, Shishido T, Sugimachi M, Alexander J Jr, Sunagawa K. Novel therapeutic strategy against central baroreflex failure: a bionic baroreflex system. Circulation. 1999;100(3):299-304.
  15. Nakahara T, Kawada T, Sugimachi M, Miyano H, Sato T, Shishido T, Yoshimura R, Miyashita H, Inagaki M, Alexander J Jr, Sunagawa K. Neuronal uptake affects dynamic characteristics of heart rate response to sympathetic stimulation. Am J Physiol. 1999;277(1 Pt 2):R140-6.
  16. Sato T, Kawada T, Inagaki M, Shishido T, Takaki H, Sugimachi M, Sunagawa K. New analytic framework for understanding sympathetic baroreflex control of arterial pressure. Am J Physiol. 1999;276(6 Pt 2):H2251-61.
  17. Kawada T, Sugimachi M, Shishido T, Miyano H, Sato T, Yoshimura R, Miyashita H, Nakahara T, Alexander J Jr, Sunagawa K. Simultaneous identification of static and dynamic vagosympathetic interactions in regulating heart rate. Am J Physiol. 1999;276(3 Pt 2):R782-9.
  18. Sato T, Kawada T, Miyano H, Shishido T, Inagaki M, Yoshimura R, Tatewaki T, Sugimachi M, Alexander J Jr, Sunagawa K. New simple methods for isolating baroreceptor regions of carotid sinus and aortic depressor nerves in rats. Am J Physiol. 1999;276(1 Pt 2):H326-32.
  19. Sato T, Kawada T, Shishido T, Sugimachi M, Alexander J Jr, Sunagawa K. Novel therapeutic strategy against central baroreflex failure: a bionic baroreflex system. Circulation. 1999; 100: 299-304.
  20. Sato T, Yoshimura R, Kawada T, Shishido T, Miyano H, Sugimachi M, Sunagawa K. The brain is a possible target for an angiotensin-converting enzyme inhibitor in the treatment of chronic heart failure. J Card Fail. 1998;4(2):139-44.
  21. Nakahara T, Kawada T, Sugimachi M, Miyano H, Sato T, Shishido T, Yoshimura R, Miyashita H, Sunagawa K. Cholinesterase affects dynamic transduction properties from vagal stimulation to heart rate. Am J Physiol. 1998;275(2 Pt 2):R541-7.
  22. Nakahara T, Kawada T, Sugimachi M, Miyano H, Sato T, Shishido T, Yoshimura R, Miyashita H, Inagaki M, Alexander J Jr, Sunagawa K. Accumulation of cAMP augments dynamic vagal control of heart rate. Am J Physiol. 1998;275(2 Pt 2):H562-7.
  23. Miyano H, Nakayama Y, Shishido T, Inagaki M, Kawada T, Sato T, Miyashita H, Sugimachi M, Alexander J Jr, Sunagawa K. Dynamic sympathetic regulation of left ventricular contractility studied in the isolated canine heart. Am J Physiol. 1998;275(2 Pt 2):H400-8.
  24. Sato T, Kawada T, Shishido T, Miyano H, Inagaki M, Miyashita H, Sugimachi M, Knuepfer MM, Sunagawa K. Dynamic transduction properties of in situ baroreceptors of rabbit aortic depressor nerve. Am J Physiol. 1998;274(1 Pt 2):H358-65.
  25. Kawada T, Sugimachi M, Sato T, Miyano H, Shishido T, Miyashita H, Yoshimura R, Takaki H, Alexander J Jr, Sunagawa K. Closed-loop identification of carotid sinus baroreflex open-loop transfer characteristics in rabbits. Am J Physiol. 1997;273(2 Pt 2):H1024-31.
  26. Matsuura W, Sugimachi M, Kawada T, Sato T, Shishido T, Miyano H, Nakahara T, Ikeda Y, Alexander J Jr, Sunagawa K. Vagal stimulation decreases left ventricular contractility mainly through negative chronotropic effect. Am J Physiol. 1997;273(2 Pt 2):H534-9.
  27. Miyano H, Kawada T, Sugimachi M, Shishido T, Sato T, Alexander J Jr, Sunagawa K. Inhibition of NO synthesis does not potentiate dynamic cardiovascular response to sympathetic nerve activity. Am J Physiol. 1997;273(1 Pt 2):H38-43.
  28. Kawada T, Sugimachi M, Shishido T, Miyano H, Ikeda Y, Yoshimura R, Sato T, Takaki H, Alexander J Jr, Sunagawa K. Dynamic vagosympathetic interaction augments heart rate response irrespective of stimulation patterns. Am J Physiol. 1997;272(5 Pt 2):H2180-7.
  29. keda Y, Kawada T, Sugimachi M, Kawaguchi O, Shishido T, Sato T, Miyano H, Matsuura W, Alexander J Jr, Sunagawa K. Neural arc of baroreflex optimizes dynamic pressure regulation in achieving both stability and quickness. Am J Physiol. 1996;271(3 Pt 2):H882-90.
  30. Ikeda Y, Sugimachi M, Yamasaki T, Kawaguchi O, Shishido T, Kawada T, Alexander J Jr, Sunagawa K. Explorations into development of a neurally regulated cardiac pacemaker. Am J Physiol. 1995; 269: H2141-6.

  1. Transneural treatment of cardiovascular disease
  2. Elaborate numerical models of biological systems: digital medicine
  3. Ultimate medicine: automated diagnosis and treatment

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