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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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

2. Elaborate numerical models of biological systems: digital medicine

Structural limitation of contemporary medicine
現代医学の構造的限界

The recent advances in medical science are truly amazing. However when mega trials (large-scale clinical investigations) in search of medical evidence are conducted aiming to validate the effects of medical treatments that have been deemed theoretically favorable from the research conducted so far, results contrary to the expectation have been revealed.

It is well known that fatal arrhythmia may occur after myocardial infarction. A clinical trial was conducted to examine whether administration of drugs that suppress arrhythmia after myocardial infarction would improve the prognosis (1989). Patients who were initially given anti-arrhythmic drugs that strongly suppress premature ventricular contraction were randomly assigned to receive active drug (anti-arrhythmic agents) or placebo, and prognosis of the two groups was compared. Surprisingly, the mortality was higher in the active drug group.

In 1991, a clinical trial was conducted to examine whether the administration of inotropic drugs for chronic heart failure would improve the prognosis. Chronic heart failure is a disease in which the contractility of heart muscles is reduced. The drug used was known to have a potent cardiotonic action from its research data. Here again, surprising result was obtained showing that the group administered the inotropic agent had significantly higher mortality compared with placebo.

At the background of these tragedies lies the fact that simply listing the elemental information (genetic, molecular, cellular) obtained from experimental biological studies does not allow us to predict collectively how a specific drug act in the complex system of the human body. To overcome this structural limitation of contemporary medicine, the Digital Medicine Initiative actively deploys computer modeling aiming to integrate all the elemental data obtained from research reports and develop a digital patient (patient in silico), an elaborate numerical human model that can be used to mimic disease conditions.


Fragmented research data
脳を造る:バイオニックブレインによる血液制御

The body is controlled by many physical mechanisms. While mechanical phenomena are important in muscles, electrical phenomena are crucial in muscle cells and neurons. On the other hand, metabolic phenomena are important in the liver and kidney. The physical quantity of each of these phenomena builds up at each level of the hierarchy; from molecular level to cellular, tissue, and system level, and collectively constitutes the human body. Therefore the information of the physical quantity at one specific level alone does not allow the prediction of how the system behaves.

Digital patient by multi-scale, multi-physics strategy
..

To understand the behaviors of this complex body system, mechanisms that integrate the various physical quantities from molecular level to system level are required. The numerical modeling techniques of recent years have opened a possibility for such approach. The current modeling has not yet reached the level we aim to attain. However, it is extremely important to develop an elaborate numerical model of the human body reconstructed from molecular level, which allows simulation of diseases. Without these integrating mechanisms, it will be difficult to effectively apply the basic research findings back to the clinical setting.


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. Ikeda 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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