In Memoriam—Dr. Hikaru Sato: The Discoverer of Takotsubo Syndrome

Michiaki Nagai; Keigo Dote; Masaharu Ishihara; Satoshi Kurisu


Eur Heart J. 2022;43(18):1693-1696. 

A pioneer of Japanese reperfusion therapy for acute myocardial infarction, the discoverer and outstanding researcher of 'Takotsubo syndrome' passed away on 10 November 2021

Dr. Hikaru Sato graduated from Kobe University in 1963. Immediately after becoming a physician, he became interested in the electrocardiographic (ECG) transformation of subarachnoid haemorrhage (SAH), and he speculated that it might be possible to diagnose SAH based on ECG findings.[1]

Post-university: Coronary angiography examinations of acute myocardial infarction initiated at Hiroshima City Hospital

Dr. Sato moved from Kobe University to Hiroshima City Hospital in 1978 (Figure 1). Cardiac surgeons at Hiroshima City Hospital had been performing angiocardiography since the early 1960s for patients in the chronic phase of heart disease,[1] and Dr. Sato was enthusiastic about studying acute myocardial infarction (AMI) patients in the coronary care unit (CCU). He suspected that the pivotal pathological condition of myocardial infarction (MI) could not be elucidated without performing coronary angiography (CAG) for patients in the acute MI phase. At that time, CAG performed in the acute phase of MI had been investigated in only a few foreign studies, and Dr. Sato's colleagues in the hospital objected based on concerns about its safety.[1]

Figure 1.

Hiroshima City Hospital in 1978, and Dr. Hikaru Sato.

In 1979–80, Dr. Sato conducted research examining whether single blood clots in a test tube would dissolve following the addition of the thrombolytic agent urokinase. The blood clots did not dissolve, but Dr. Sato persisted; he compiled all of the existing literature on urokinase to determine why the blood clots did not dissolve. He speculated that if urokinase was infused intravenously, the presence or absence of the effect could be evaluated by CAG or by left ventriculography (LVG).

In 1979, Dr. Klaus Peter Rentrop at Göttingen University succeeded in the recanalization of AMI patients' occluded coronary arteries by applying a selective intracoronary administration of streptokinase under angiography.[2] In light of that report, Dr. Sato realized that the solution to his above-mentioned in vitro research might be obtained if he performed CAG and LVG before and after an intracoronary administration of urokinase in a patient with AMI. He had been informed that Dr. Masakiyo Nobuyoshi at Kokura Memorial Hospital injected urokinase into a patient's aortic bulb for the first time in Japan, and he decided to try infusing urokinase directly into a coronary artery, in 1981. In the first case, 480 000 units of urokinase were infused; the thrombosis dissolved as he watched (Figure 2).[3] His further results demonstrated that conducting CAG and LVG in patients in the acute phase of MI was safe and effective as long as the procedures were performed carefully. Dr. Keigo Dote, the president of Hiroshima City Asa Hospital, later presented an introduction to intracoronary thrombolytic therapy in AMI at an annual meeting of the American College of Cardiology.

Figure 2.

The first use of emergency coronary angiography for acute myocardial infarction at Hiroshima City Hospital, on 26 May 1981. Control contrast shows complete occlusion of the left anterior descending artery (left). After an intracoronary infusion of urokinase, recanalization was observed without contrast delay (right). Reconstructed from Ishihara and Sato3.

Encounters with Dr. Hirofumi Yasue and Dr. Saichi Hosoda, and the discovery of Takotsubo syndrome

A few years later, Dr. Hirofumi Yasue, who worked to reveal the pathophysiology of vasospastic angina in the 1970s at Shizuoka Municipal Hospital, came to Hiroshima to give a lecture. Dr. Yasue was the clinician that Dr. Sato admired most because Dr. Yasue had shown the importance of work outside the university, and Dr. Sato was greatly influenced by Dr. Yasue's stance regarding clinical investigations. Dr. Saichi Hosoda, who established the Japanese CCU system at Tokyo Women's Medical University, taught medical statistics for clinical research and greatly encouraged Dr. Sato.[1]

During the many years that Dr. Sato pursued his passion to determine the pathophysiology of AMI, he encountered a patient with left ventricular (LV) apical ballooning shown by LVG, without coronary artery stenosis. Surprisingly, the LVG revealed akinesis in the mid- to the apical portion of the LV with vigorous contraction of the basal segment, which could not be explained by a single branch lesion. Soon after, Dr. Sato discussed the case with Dr. Dote, and Dr. Sato named the syndrome 'Takotsubo cardiomyopathy' (Takotsubo syndrome: TTS) because on LVG, the patient's end-systolic LV apical ballooning resembled a Japanese traditional octopus trap, i.e. a takotsubo. In 1983, the first case of TTS at Hiroshima City Hospital was documented (Figure 3),[1,4] and three and five additional cases were reported in 1990[5] and 1991,[6] respectively.

Figure 3.

The first diagnosed case of Takotsubo syndrome (23 September 1983). No stenosis or occlusion was observed in coronary angiography after an intracoronary nitroglycerin infusion (left). Left ventriculography revealed a characteristic 'takotsubo'-like end-systolic LV morphology (right); with permission from Sato and Yamashina1.

Although the peculiar wall motion of the LV in Dr. Sato's initial TTS patient disappeared within about 2 weeks, the coronary vasospasm was considered the pivotal pathophysiology in the acute phase of the patient's TTS. At the first annual meeting of the Japanese Coronary Association, Dr. Dote explained the case and presented a cine film of the CAG and LVG results. Dr. Sato felt that Dr. Dote's explanation was excellent and quite memorable, as he clearly remembers that the large audience seemed taken aback when the coronary artery was projected with a thin thread-like image under a load of ergometrine in the acute phase of TTS. As shown by subsequent reports, a load of ergometrine present in the acute phase is extremely rare, while the results in the chronic phase of TTS denied a coronary artery spasm. In his following extensive research regarding TTS, Dr. Sato was blessed with the cooperation of excellent physicians such as Dr. Hironobu Tateishi, Dr. Dote, Dr. Takuji Kawagoe, Dr. Masaharu Ishihara, and Dr. Satoshi Kurisu, who are part of the younger generation leading the Japanese Society of Cardiology. Takotsubo syndrome is now known worldwide as a transient weakening of the LV, triggered by emotional or physical stress such as a sudden illness, the loss of a loved one, a serious accident, or a natural disaster such as an earthquake.[4,7–9]

On 10 November 2021, we received a message that Dr. Hikaru Sato, the discoverer of TTS who had been a leader in TTS research for many years, passed away peacefully. As his pupils, we are profoundly saddened by his death.

We seek to carry on Dr. Sato's seminal research. In his later years, he mentioned that the ECG change of SAHs had suddenly come to his attention when he thought about TTS. Inspired by the mentorship of Dr. Hikaru Sato, we have taken a group oath to pursue the elucidation of the pathophysiology of TTS from the viewpoint of the brain–heart axis.[10] We regret that he did not live to see this discovery, and we very much miss our discussions on his original ideas.