Smart Closed-loop Neuromodulation Revolutionizes Cardiology in the 21st Century
In the last few decades, tremendous progress has been made in cardiology. Although molecular biology is a major driving force of this progress, technology plays a crucial role. We witness in daily patient care that sophisticated devices such as cardiac defibrillators, pacemakers, circulatory assist devices, percutaneous coronary intervention and ablation save many lives. However there is no doubt that only a little of the potential of technology has been explored. The key element that prevents full exploration would be the lack of unification of high-tech based therapeutic systems into natural human physiology. In the human body, all cells, tissues, organs, and systems operate coherently. The presence of well-developed neuro-humoral communications among these components of the body is the essential infrastructure that makes coherent functioning possible. If we could incorporate such communication mechanisms into artificial systems, they would function as if they are an integral part of the native physiological systems. We call such well-integrated smart artificial systems bionic systems. Cardiology utilizing smart bionic systems is bionic cardiology.
The bread-and-butter technology that is common to all bionic systems is the technique to unify the artificial devices with the native systems, in particular, the human body’s regulatory systems. In 1996, we developed one such system, a neurally regulated cardiac pacemaker. The success of the neurally regulated pacemaker has convinced us that the autonomic system can be effectively monitored and thereby electrically manipulated. The clinical impact of direct manipulative neuromodulation of autonomic functions in cardiovascular diseases is profound. Virtually every cardiovascular disease has a major problem in its autonomic regulation. The case of central baroreflex failure is an archetypal example. The bionic baroreflex system operates as an intelligent negative feedback regulator. We demonstrated in animals and in patients that the bionic baroreflex system restores normal baroreflex function. The bionic baroreflex system opens up an entirely new therapeutic modality for patients with baroreflex failure. In our latest investigation, we demonstrated that bionic manipulative closed-loop neuromodulation of autonomic functions is extremely powerful in the management of refractory hypertension, acute myocardial infarction and heart failure.
Bionic medicine aims at improving clinical outcomes and enhancing quality of life by restoring the lost functions of failing physiological systems or organs. The combination of latest technology, biology and quantitative systems physiology, all of which are progressing very rapidly, will inspire even more intricate disruptive innovations of bionic medicine in the 21st century.
Kenji Sunagawa, MD, PhD is the founder and Professor of the Center for Disruptive Cardiovascular Medicine (CDiC) at Kyushu University, Fukuoka, Japan. CDiC is the institution to develop future medicine via disruptive innovations to save patients with treatment refractory cardiovascular disease.
Dr. Sunagawa received his M.D. in 1974 and Ph.D. in 1986 from Kyushu University, Fukuoka, Japan. He joined the cardiovascular group at the Department of Biomedical Engineering, Johns Hopkins in 1978 and contributed to establish the concept of the pressure-volume relationship of the heart, one of the most fundamental concepts of cardiac mechanics. In 1990, he was appointed chairman of the Department of Cardiovascular Dynamics as well as the Division of Cardiology at the National Cardiovascular Center in Osaka. In 2004, he was appointed Professor and Chief of Cardiology Division and Chairman of Cardiovascular Medicine at Kyushu University. He has been extensively applying the concept of engineering to study cardiac mechanics and cardiovascular neural regulation. Those studies have led him to develop intelligent neuromodulators (i.e., bionic systems) that are interfaced and functionally unified with the native autonomic nervous system. Since the late 90s, he developed a neurally regulated cardiac pacemaker, bionic baroreflex system and bionic cardiac neuromodulator, all of which had striking impacts on the management of refractory cardiovascular disease. Because of these contributions, he received the Paul Dudley Lectureship Award from American Heart Association in 2000 and EMBS Technical Award in 2010. He served as AdCom member and chair of Technical Committee on cardiopulmonary systems of EMBS. He hosted the EMBC2013 in Osaka as the conference chair. He was a board member of the Japanese Society for Medical and Biological Engineering and the Japanese Society of Internal Medicine. He is a Fellow of American Heart Association, American College of Cardiology and European Society of Cardiology.
Prof. Sunagawa received his M.D. in 1974 and Ph.D. in 1986 from the Kyushu University, Fukuoka, Japan. From 1978 to 1983, he was a postdoctoral fellow and then appointed the faculty at the Department of Biomedical Engineering and Division of Cardiology, Johns Hopkins Medical Institutions. From 1990 to 2004, he chaired the Department of Cardiovascular Dynamics at the National Cardiovascular Center in Osaka. Since 2004, he has been the Chief and Professor of Cardiovascular Medicine at the Kyushu University. He has extensively applied engineering concepts to study cardiovascular regulation. Those studies led him to develop bionic cardiology. Bionic systems function just like native physiological systems. Since late 90s, he developed a neurally regulated pacemaker, bionic baroreflex system and bionic neurostimulator for heart failure, all of which had striking impacts in treating refractory cardiovascular diseases. Because of this contribution, he received the Paul Dudley White Award from the American Heart Association (AHA) in 2000. He has been a fellow of AHA, American College of Cardiology and European Society of Cardiology. He is a board member of Japanese Society for Medical and Biological Engineering, a senior member of IEEE, and a member of AdCom of EMBS since 2005.
Major scientific contributions
In the 70s and early 80s, Dr. Sunagawa and his colleagues demonstrated that cardiac elastic properties vary with cardiac cycle, and that the ventricle can be modeled by a time-varying elastance. Ventricular elastance is remarkably insensitive to loading conditions, and end-systolic elastance is an excellent load-independent index of cardiac contractility. In the early 1980’s, he developed an ingenious servo-pump system to impose hemodynamic impedance on isolated ventricles and to study the load insensitivity of ventricular elastance. Furthermore, Dr. Sunagawa established the concept of ventricular-arterial coupling. He proposed the use of “effective arterial elastance” to translate viscous properties of the arterial system into elastic properties and made it possible to derive the analytical solution of stroke volume for a given heart. Elastance and ventricular-arterial coupling have become classic concepts and are now taught at medical schools worldwide.
Dr. Sunagawa has also applied engineering principles to the quantitative analysis of cardiovascular regulation. The analysis of physiological systems is a system identification problem involving complex nonlinear and time varying systems. He has been using white noise approaches to identify the dynamic transfer functions of several target systems. After completing functional identification, he proceeds to structural identification. The presence of nonlinearity often helps him understand the internal structure of a system. He applied this concept to baroreflex regulation of the cardiovascular system and demonstrated that the open-loop transfer function has complex and non-linear dynamic properties. His team also demonstrated that the presence of derivative characteristics in the central baroreflex loop was a prerequisite for quick yet stable regulation of blood pressure. His group also demonstrated that the vagal sympathetic systems augment respective gain of heart rate control, thereby expanding the dynamic range of heart rate regulation. Those quantitative analyses using engineering concepts led him to the development of bionic cardiology. He has published important papers in this developing field in many journals including more than 50 in the American Journal of Physiology.
In the body every cell, tissue, organ, or system operates coherently, and this requires the presence of a well-developed neuro-humoral communication infrastructure. Hence if we could implement similar mechanisms into artificial devices, they would function more like parts of native physiological systems. Dr. Sunagawa calls such devices bionic systems. Unification of an artificial system with the native system requires bidirectional communications. In 1996, Dr. Sunagawa developed a neurally regulated artificial pacemaker (Am J Physiol 1996). He demonstrated that the instantaneous sinus rate was determined not only by the current sympathetic activity but also by its history. He quantified the history dependence in terms of an impulse response by deconvolving the heart rate response with sympathetic nerve activity. Using the convolution integral of the impulse response with the instantaneous sympathetic activity, he could predict the precise heart rate real-time.
The success of the neurally regulated bionic pacemaker has convinced him that the autonomic system can be effectively monitored and thereby manipulated by bionic systems. The loss of blood pressure control is an archetypal example of one such application. In treating this disease, Dr. Sunagawa implemented an artificial bionic baroreflex system as biological proxy capable of emulating the proper function of the failing vasomotor center. The bionic baroreflex system consists of a pressure sensor (baroreceptor), microprocessor (vasomotor center) and nerve stimulator (for activation of sympathetic efferents). The system operates as an intelligent negative feedback regulator, and has been demonstrated effective in restoring normal baroreflex function in animals (Circulation 1999, 2002). This approach represents an entirely new therapeutic modality for patients with baroreflex failure.
Following those investigations, Dr. Sunagawa applied the bionic technology in treating heart failure where excessive central activation has deleterious effects on the failing heart. So, instead of letting the brainstem control the heart, he implanted a small device attached to the cardiac vagal nerve to control the autonomic tone of the heart. The results were impressive. The survival rate at 20 weeks (rat) was 50% with native autonomic regulation, and was 90% with bionic treatment (Circulation 2004). Bionic medicine thus aims to improve quality of life by restoring normal function to failing physiological systems or organs. Because of these contributions, Dr. Sunagawa won the Paul Dudley White Lectureship Award of American Heart Association and the Isaac Starr Lectureship Award of the Cardiovascular System Dynamics Society in 2000, and was inducted into the Society of Scholars of the Johns Hopkins University in 1997.