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Cardiac Arrhythmia and Respiratory Dysfunction

There is a vast room for improvement in the diagnosis and treatment of lethal arrhythmia. Taking advantage of our mathematical engineering background, we have been investigating the mechanisms of arrhythmia under various pathophysiological conditions with use of the computer simulation and the optical mapping technique. Sleep apnea syndrome has been reported to be associated with various cardiovascular disorders (hypertension and ischemic heart disease). Respiratory dysfunction has become an important therapeutic target in clinical cardiology. Therefore, we are conducting studies on the associations between the respiratory dysfunction and progression of heart failure.

(1) Studies on Arrhythmogenesis Using Whole Heart Computer Simulation

We are developing a whole heart computer simulator that reproduces anatomical, electrophysiological, and mechanical characteristics of the heart by integrating the subcellular and cellular components. Since this simulator includes all thoracic organs such as the lung and the aorta, it can reproduce laboratory findings obtained by surface ECG or trans-thoracic echocardiography. This simulator allows extensive analysis of key patho-physiological mechanisms of arrhythmogenesis. Evaluation of therapeutic effects of a variety of procedures by the simulator enables us to develop a novel therapeutic modality or procedure such as a highly-effective electrical defibrillator. (Collaboration with researchers of the University of Tokyo.)

(2) Optical Mapping of Cardiac Excitation

Spatio-temporal electric heterogeneity of heart is one of the key factors to initiate ventricular fibrillation. Using voltage-sensitive fluorescent dye and high-speed photodetectors (CMOS), we succeeded in mapping action potentials with a very high resolution both in time and space. Furthermore, we developed a method to record action potentials from a freely beating (contracting) heart. Using our system, we were able to evaluate the effect of mechano-electrical coupling on the electric activity of the heart.


  1. Aiba T, Shimizu W, Hidaka I, Uemura K, Noda T, Zheng C, Kamiya A, Inagaki M, Sugimachi M, Sunagawa K. Cellular basis for trigger and maintenance of ventricular fibrillation in the Brugada syndrome model: high-resolution optical mapping study. J Am Coll Cardiol 47: 2074-2085, 2006.
  2. Seo K, Inagaki M, Nishimura S, Hidaka I, Sugimachi M, Hisada T, Sugiura S. Structural heterogeneity in the ventricular wall plays a significant role in the initiation of stretch-induced arrhythmias in perfused rabbit right ventricular tissues and whole heart preparations. Circ Res 106: 176-184, 2010.
  3. Inagaki M, Hidaka I, Aiba T, Tatewaki T, Sunagawa K, Sugimachi M. High resolution optical mapping of cardiac action potentials in freely beating rabbit hearts. Conf Proc IEEE Eng Med Biol Soc. 2004;5:3578-80.

(3) Electrical Heterogeneity of Cardiac Action Potentials and Arrhythmias

The regional differences in the electrophysiological properties of the ventricular myocardium have been well established. Our experimental study using an arterially-perfused feline wedge demonstrated that repolarization of the briefest action potential (AP) in the epicardium coincided with the peak of ECG T wave, whereas the longest AP in the M region coincided with the end of the T wave. The repolarization of the endocardium was intermediate between that of epicardium and M regions. Moreover, we elucidated the cellular and ionic mechanisms of drug-induced long-QT syndrome and the effect of verapamil. Thus, the electrophysiological heterogeneity across the ventricular wall produced the inscription of the normal and abnormal T wave and was responsible for the occurrence of ventricular tachyarrhythmias. Using a similar experimental setup, we also examined the mechanisms underlying polymorphic ventricular tachycardia associated with the Brugada syndrome.


  1. Aiba T, Inagaki M, Shimizu W, Matsuo K, Taguchi A, Suyama K, Kurita T, Aihara N, Sunagawa K, Kamakura S: Recovery time dispersion measured from 87-lead body surface potential mapping as a predictor of sustained ventricular tachycardia in patients with idiopathic dilated cardiomyopathy. J Cardiovasc Electrophysiol 11: 968-974, 2000.
  2. Shimizu W, Tanabe Y, Aiba T, Inagaki M, Kurita T, Suyama K, Nagaya N, Taguchi A, Aihara N, Sunagawa K, Nakamura K, Ohe T, Towbin JA, Priori SG, Kamakura S: Differential effects of beta-blockade on dispersion of repolarization in the absence and presence of sympathetic stimulation between the LQT1 and LQT2 forms of congenital long QT syndrome. J Am Coll Cardiol 39: 1984-1991, 2002.
  3. Aiba T, Shimizu W, Inagaki M, Hidaka I, Tatewaki T, Sunagawa K: Transmural heterogeneity of the action potential configuration in the feline left ventricle. Circ J 67: 449-454, 2003.
  4. Aiba T, Shimizu W, Inagaki M, Noda T, Miyoshi S, Ding WG, Zankov DP, Toyoda F, Matsuura H, Horie M, Sunagawa K. Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil. J Am Coll Cardiol 45: 300-307, 2005.

(4) Arrhythmia and Autonomic Nerve Activity

Activation of autonomic nerve such as sympathetic and vagal nerves modulates myocardial action potential duration (APD) of the ventricle. In response to sudden sympathetic activation, APD was transiently prolonged for approximately 15 s, and monotonically shortened toward a steady-state level. The transient prolongation and steady-state shortening of APD would favor the onset of ventricular arrhythmia. The fact that propranolol and vagal nerve stimulation almost abolished both the transient prolongation and the steady-state shortening suggests the important role of the autonomic nervous system in a therapeutic strategy against lethal ventricular arrhythmias.


  1. Tatewaki T, Inagaki M, Kawada T, Shishido T, Yanagiya Y, Takaki H, Sato T, Sugimachi M, Sunagawa K: Biphasic response of action potential duration to sudden sympathetic stimulation in anesthetized cats. Circ J 67: 876-880, 2003.

(5) Effect of the mechanical load on arrhythmogenesis

Alterations to the mechanical state of the myocardium affect its electrophysiological properties, a phenomenon termed mechanoelectric feedback (MEF). MEF is considered to play a significant role in the genesis of cardiac rhythm disturbances in myocardial infarction and sudden death owing to a chest wall impact. We applied volume pulses to the isolated perfused rabbit right ventricle, and investigated the arrhythmogenesis by the mechanical loads. We found that when the propagation of the focal excitations induced by medium-sized mechanical stimuli interacts with the preceding electric activations, it can develop to fatal reentrant arrhythmias. Computer simulation disclosed that the mechanical load maintains the ventricular fibrillation by destabilizing and repeatedly dividing the fibrillation waves.


  1. Seo K, Inagaki M, Nishimura S, Hidaka I, Sugimachi M, Hisada T, Sugiura S. Structural heterogeneity in the ventricular wall plays a significant role in the initiation of stretch-induced arrhythmias in perfused rabbit right ventricular tissues and whole heart preparations. Circ Res 106: 176-184, 2010.
  2. Hirabayashi S, Inagaki M, Hisada T, Sugimachi M. Effects of wall stress on the dynamics of ventricular fibrillation,"Mechanosensitivity in Cells and Tissues: Mechanosensitivity of the Heart" (eds. Andre Kamkin & Irina Kiseleva)、SPRINGER VERLAG 2009.
  3. Hirabayashi S, Inagaki M, Hisada T. Effects of wall stress on the dynamics of ventricular fibrillation: A simulation study using a dynamic mechanoelectric model of ventricular tissue. J Cardiovasc Electrophysiol. 19(7): 730-9, 2008.

(6) Relationship Between Abnormal Ventilatory Pattern (Periodic Breathing) and Prognosis of Heart Failure

In patients with heart failure, abnormal ventilatory pattern that waxes and wanes periodically is occasionally observed. The periodic breathing is frequently observed when patients with severe heart failure perform a light exercise. We examined whether this sign is related to the prognosis of heart failure. As a result, although 58% of the patients with the periodic breathing required hospitalization in three years, only 8% of the patients without the periodic breathing did so. We are able to provide more fine treatment by predicting the severity of heart failure from breathing patterns.

(7) Development of a Quantitative Examination for Respiratory Regulation in Heart Failure Patients

In patients with heart failure, abnormal ventilatory patterns such as an enhanced ventilatory response to exercise happen occasionally. The respiratory regulation is performed by sensing the concentration of CO2 in arterial blood (PaCO2) and/or pH. Because the unnecessarily augmented breathing is considered to relate to the abnormal respiratory regulation in patients with heart failure, a quantitative examination method for abnormal respiratory regulation should be developed.

In normal subjects, we first measured the increment of respiration in response to the increase in PaCO2 achieved by an inspiration of high CO2 content gas. Next, we measured the decrease in PaCO2 by hyperventilation. The two data sets were combined in a equilibrium diagram of the respiratory regulation. This method will be improved and simplified to examine the respiratory regulation in patients with heart failure.


  1. Miyamoto T, Inagaki M, Takaki H, Kawada T, Yanagiya Y, Sugimachi M, Sunagawa K. Integrated characterization of the human chemoreflex system controlling ventilation, using an equilibrium diagram. Eur J Appl Physiol 93: 340-346, 2004.
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