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Bionic Cardiology

In Japan, heart transplantation has become one of the standard therapeutic modalities to treat patients with severe heart failure; however, the availability of donor hearts is limited. Another option is the artificial heart. As the host body does not directly control the artificial heart presently in clinical use, the prosthesis does not always work in concert with the host body. To solve this, an artificial heart must exchange various forms of information with its host body. Bionic medicine aims at achieving such artificial organs. Because information is rapidly transmitted through the nervous system to all organs throughout the body, various bionic organs can be actualized if information can be exchanged between the organs and the host nervous system, including the brain. It is feasible to develop an artificial organ controlled by the host body using nerve activity, or to replace part of the biological control system with a microprocessor. We have succeeded in treating animal models of heart failure by electronically regulating the activity of parasympathetic nervous system. We have also successfully developed the logical interface necessary for controlling blood pressure and heart rate, and are now developing a nerve regeneration electrode for the physical interface.

(1) Bionic Treatment of Chronic Heart Failure

In severe myocardial infarction sympathetic nerve activity persistently increases in response to the depression of cardiac function and/or activation of pathological reflexes in the chronic period. The persistent sympathetic hyperactivity causes cardiac enlargement (cardiac remodeling), leading to death from heart failure. We therefore examined whether chronic vagal stimulation that would counteract to the sympathetic hyperactivity could prevent cardiac remodeling and improve the survival rate in rats with myocardial infarction.

When we stimulated the rat vagus from 2 to 6 weeks after myocardial infarction, the cardiac remodeling was prevented. Twenty weeks observation indicated that the survival rate was markedly improved by vagal stimulation. In myocardial ischemia-reperfusion model (cat and rabbit), short-term vagal nerve stimulation attenuated myocardial injury and prevented the progression to heart failure. Because the vagal stimulation could be a novel therapeutic approach for heart failure irrespective of whether heart failure is caused by myocardial infarction, the ongoing study aims its clinical application. In addition, we are examining the treatment of heart failure using a bionic autonomic control via baroreflex as an alternative to the vagal stimulation treatment.

References:

  1. Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K: Vagal nerve stimulation markedly improves long-term survival of chronic heart failure in rats. Circulation 109: 120-124, 2004.
  2. 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. 156: 71-75, 2006.
  3. Uemura K, Li M, Tsutsumi T, Yamazaki T, Kawada T, Kamiya A, Inagaki M, Sunagawa K, Sugimachi M. Efferent vagal nerve stimulation induces tissue inhibitor of metalloproteinase-1 in myocardial ischemia-reperfusion injury in rabbit. Am J Physiol Heart Circ Physiol 293: H2254-2261, 2007.
  4. Kawada T, Yamazaki T, Akiyama T, Kitagawa H, Shimizu S, Mizuno M, Li M, Sugimachi M. Vagal stimulation suppresses ischemia-induced myocardial interstitial myoglobin release. Life Sci 83: 490-495, 2008.
  5. Kawada T, Akiyama T, Shimizu S, Kamiya A, Uemura K, Li M, Shirai M, Sugimachi M. Detection of endogenous acetylcholine release during brief ischemia in the rabbit ventricle: a possible trigger for ischemic preconditioning. Life Sci 85: 597-601, 2009.
  6. Uemura K, Zheng C, Li M, Kawada T, Sugimachi M. Early short-term vagal nerve stimulation attenuates cardiac remodeling after reperfused myocardial infarction. J Card Fail 16: 689-699, 2010.

(2) Development of Bionic Baroreflex System

The human body has a control system that maintains near constant arterial pressure, i.e., the baroreflex system, which works through negative feedback. This system attenuates blood pressure variations caused by perturbation to the body, and operates steadily to counteract extreme variations in blood pressure caused by postural changes. In patients with Shy-Drager syndrome, significant blood pressure variation with changes in body position (hypotension in standing position and hypertension in supine position) greatly aggravates the quality of life. By replacing the damaged baroreflex system with a bionic baroreflex system, blood pressure may be kept stable in such patients.

In model animals with blocked baroreceptor afferent, we studied variation in blood pressure by having the animals stand up with and without the bionic baroreflex system. Hypotension caused by standing became transient and was attenuated with bionic baroreflex system operation, which was functionally indistinguishable from natural blood pressure stabilizing action. We have developed epidural stimulation method and hind-limb electroacupuncture method as actuators of the bionic baroreflex system. These findings suggest that blood pressure stabilizing action in normal animals can be reproduced through functional replacement of the natural vasomotor center with an artificial one.

References:

  1. Sato T, Kawada T, Shishido T, Sugimachi M, Alexander J Jr, Sunagawa K: A novel therapeutic strategy against central baroreflex failure: a bionic baroreflex system. Circulation 100: 299-304, 1999.
  2. Sato T, Kawada T, Sugimachi M, Sunagawa K: Bionic technology revitalizes native baroreflex function in rats with baroreflex failure. Circulation 106: 730-734, 2002.
  3. 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 97: 984-990, 2004.
  4. Kawada T, Shimizu S, Yamamoto H, Shishido T, Kamiya A, Miyamoto T, Sunagawa K, Sugimachi M. Servo-controlled hind-limb electrical stimulation for short-term arterial pressure control. Circ J 73: 851-859, 2009.

(3) Development of Bionic Cardiac Pacemaker

The artificial cardiac pacemaker is a function-supporting device traditionally used in bradycardiac patients; however, there is room for improvement regarding support of the natural heart rate. The rate-responsive cardiac pacemaker, which has been developed, estimates the natural heart rate from the QT interval in ECG, body temperature, acceleration, etc., and changes the rate accordingly. However, the estimated rate is not necessarily specific, sensitive or correct in terms of transient response. The human body uses autonomic nerve activity to control heart rate. A cardiac pacemaker that could change the rate on the basis of nerve activity would be the ideal artificial cardiac pacemaker, capable of reproducing the natural heart rate at all times.

We have developed an artificial cardiac pacemaker that translates cardiac sympathetic nerve activity and changes the pacing rate accordingly. Although instantaneous sympathetic nerve activity itself does not directly correlate with the instantaneous heart rate, we succeeded in retrieving heart rate by decoding nerve activity based on a translation rule (transfer function). This enables the bionic cardiac pacemaker to reproduce the natural human heart rate, changing the rate on the basis of sympathetic nerve activity.

References:

  1. 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 269: H2141-H2146, 1995.

(4) Development of Nerve Regeneration Electrode

Bionic cardiology requires a means of establishing a steady exchange of information between nervous system and device, over an extended period. To establish a physical interface with the peripheral autonomic nervous system, a nerve regeneration electrode using a micromachine technique is now under development. It is known that nerve fibers can regenerate through holes in an electrode that are placed in contact with both ends of the cut nerve. Further, nerve electrical activity can be recorded using the electrodes through which the nerves have regenerated. We have been developing electrodes on the basis of this principle, and have confirmed nerve regeneration and electrical activity transmission across the cut ends. Currently, we are investigating in experimental animals whether nerve activity can be steadily recorded with the electrodes over long periods of time.

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