It is a great honour for me to write about Atsuyoshi Takao (Fig. 1) on the occasion of his induction to the Paediatric Cardiology Hall of Fame. It is also very sad for me to announce that he passed away on August 8, 2006, at the age of 81. Everyone would agree that he was one of the most creative and active paediatric cardiologists in the world. Although he had officially retired, he was still seeing many patients at an outpatient clinic on the day before he was admitted to the hospital. He had back pain on August 1, 2006, and was admitted to the hospital the next day. An emergency coronary angiogram showed total occlusion of the left anterior descending artery. After percutaneous coronary intervention, he was busy reading medical papers in bed in the hospital when, on August 8, he died suddenly due to rupture of the left ventricular wall.
Atsuyoshi Takao. He wrote as “Development, Unfolding”.
I first met Atsuyoshi Takao in 1974, when I graduated from Hiroshima medical school. I visited the Heart Institute of Japan and asked Dr Takao to allow me to come to the Institute after I finished my paediatric residency. At that time, he was already a famous paediatric cardiologist in Japan. In those days, he was a great professor, and in keeping with the Japanese tradition, I could not speak with him frankly. He was not a person who would talk freely for a long time. Just a short conversation every day was his style. I remember he used to say that “It is best to work with originality, it is second best to do some work anyway, and it is the worst to disturb colleagues from doing their work”. Now, I always try to follow his advice.
In 1977, I left the Heart Institute to work as a research fellow at the University of California at Los Angeles. While I was in the United States, Dr Takao sent me several letters. In one of them, he said that, rather unexpectedly, he had become the director of the Heart Institute of Japan. Traditionally, the Heart Institute of Japan had been led by either a cardiac surgeon or a cardiologist. He did an excellent job as the director of the institute. He showed well-balanced leadership among cardiac surgeons, cardiologists, and paediatric cardiologists. After I returned from the United States of America, I spent more time with him, and gradually began to know him better, finding that he was an honest, sincere, and warm person.
In March,1990, Atsuyoshi Takao retired from the position of professor of paediatric cardiology (Fig. 2). During the lecture made on his retirement, he read a poem composed by a young boy named Kou Murakami. The child had a congenitally malformed heart, had undergone a palliative operation, and died with his mother at his side when he was only an elementary school student.
Atsuyoshi and Yukie Takao at the retirement party in 1990.
I will present the poem “My treasure”, which I have translated into English.
Dr Takao could not read the poem to the end without tears in his eyes. At that moment, I felt that, for Dr Takao as for Kou Murakami, each day was his treasure, and he also lived that way.
Education
Atsuyoshi was born in 1925. The Takaos originate from an ancestor who started to serve as local ruler in Kyushu Island, one of 170 daimyo under the Shogun, in the Edo era, about 370 years ago. The Takaos had been doctors for the rulers during the Edo era. Atsuyoshi’s grandfather moved to Tokyo at the end of the Edo era as a doctor. His father opened a private clinic in the centre of Tokyo, and had nine children, including Atsuyoshi. His father died early, and the family had to move back to Kyushu, because it was easier for the family to live there among relatives. Atsuyoshi went to high school and medical school in Nagasaki, in Kyushu. Of the 9 children, 6 became medical doctors. Kazuo Momma, a professor emeritus of paediatric cardiology in our institute, was a classmate of Atsuyoshi’s youngest brother, who is now an ophthalmologist, at Tokyo University.
Atsuyoshi Takao graduated from Nagasaki medical school in 1945. After graduation, during the Second World War, he served at the army medical school. He was in Yamagata prefecture, the northern part of the main island of Japan, when the atomic bomb was dropped in Nagasaki, and the War ended in August, 1945. He studied general paediatrics at Nagasaki and Yamaguchi medical schools for 5 years. In 1950, he started to work at the Atomic Bomb Casualty Commission in Nagasaki, serving as an assistant in the Division of Pediatrics. At that time, James Yamazaki, a clinical professor at the University of California at Los Angeles and an author of “Children of the Atomic Bomb” was working in Nagasaki. About 30 years later, I drove Atsuyoshi to meet Dr Yamazaki in Los Angeles, and we had an enjoyable time together. Atsuyoshi worked at the Atomic Bomb Casualty Commission in Nagasaki and Hiroshima for two years.
In 1952, Atsuyoshi went to New York University to train in general paediatrics (Fig. 3). He travelled to the west coast of America by ship, and from Los Angeles to Chicago by train named El Captain. He did not talk very much about the details of his life in the United States of America while I worked with him, and I can only guess that he worked hard. He was certainly well trained as a paediatrician, because he had profound knowledge of general paediatrics. He spent four years at New York University. After finishing his residency, he went to Texas Children’s hospital, where Dan G McNamara was the chief, and where he spent 3 years as a clinical fellow in pediatric cardiology. Later in life, Atsuyoshi met Richard Van Praagh. Both Richard and Dan had finished their clinical fellowships at Johns Hopkins University, and they knew each other from reunion parties. Since Richard and Dan were good friends, Richard felt instantly that Atsuyoshi was his friend, too (Fig. 4). Later, in 1971, Helen Taussig visited our institute to give a lecture to the students of Tokyo Women’s Medical University (Fig. 5). The friendship of Atsuyoshi and Richard continued, and we were gratified that Richard was able to visit our institute in 2006 for the memorial service of Atsuyoshi Takao.
Atsuyoshi Takao at New York University in 1962.
Stella and Richard Van Praagh, Atsuyoshi Takao, and Young Chang Tockgo at the Takao meeting in 1988.
Atsuyoshi Takao, Helen Taussig, and Shigeru Sakakibara at Tokyo Women’s Medical University in 1971.
The Heart Institute of Japan
The Heart Institute of Japan was founded in 1955, and the first closure of atrial septal defect in Japan was performed at the Institute in 1956. Although many patients underwent cardiac surgery, the operative results were unfavourable and the indication for operation was unclear. This was not unlike the situation prevailing in many other countries at that time.
When Atsuyoshi came back to Japan, in 1958, Shigeru Sakakibara, the first chief cardiac surgeon, and founder of the Heart Institute of Japan, invited him to become Assistant Professor at the Department of Cardiac Surgery. Among surgeons, he soon showed his ability to make correct diagnoses from physical findings, electrocardiograms, and chest X-rays. He wondered, however, if he should continue to send patients to surgery, knowing that the rate of mortality was very high, and that Dr Sakakibara insisted on performing intracardiac repair, rather than palliation, even with the high mortality rate. In this respect, Atsuyoshi was not loyal to the Institute, and sent some patients to other hospitals, with better results.
He became the professor, and chief, of paediatric cardiology in 1968. In the 1970s, Souji Konno and Yasuharu Imai started to operate on children with congenitally malformed hearts, and the operative results improved significantly. Kazuo Momma and Masahiko Ando joined the Department of Pediatric Cardiology, and the number of clinical fellows increased gradually. As the operative results improved, the reputation of the Heart Institute, along with that of Dr Takao, became widespread, and he attracted many patients from all over Japan (Fig. 6).
Atsuyoshi Takao at the pediatric ward in 1978.
Marriage
On visiting the pediatric ward one day, Atsuyoshi met a pediatrician, named Yukie. In 1962, they got married. Yukie Takao then worked at a centre for public health until 1990, when both Yukie and Atsuyoshi retired. Subsequent to their retirement, they both enjoyed hiking and mountain walking together in the suburbs of Tokyo.
Hokkaido hot springs
Every summer, doctors who finished their fellowship and returned to their hometown in Hokkaido, a northern island of Japan, invited Atsuyoshi and Yukie to go mountain hiking. There are many hot springs in Hokkaido, and Atsuyoshi and Yukie enjoyed the hotsprings in the mountains very much (Fig. 7). Once, the fellows organized a sushi party at the top of a mountain. They brought fish, and asked a sushi master to climb the mountain with them. Dr Takao did not want the fellows to pay the expenses so he sent more than enough money in advance for the party.
Atsuyoshi, enjoying Shiatsu massage by an ex-fellow Isamu Hamada.
Conotruncal anomaly face syndrome, or the Takao syndrome
In 1965, DiGeorgeReference Cooper, Peterson and Good1 commented on an infant with hypoparathyroidism and recurrent infections, along with 3 autopsied cases with absence of the thymus and parathyroid glands. Later, the association of cardiovascular abnormalities, such as interruption of the aorta, common arterial trunk, and tetralogy of Fallot, with DiGeorge syndrome was established by the work of Freedom and colleaguesReference Freedom, Rosen and Nadas2 and Van Mierop and Kutsche.Reference Van Mierop and Kutsche3 From early 1980s, deletion of chromosome 22q11 started to be recognized as a cause of the syndrome,Reference de la Chapelle, Herva, Koivisto and Aula4 and microdeletion of this region was confirmed in 1991 and 1992.Reference Wilson, Cross and Goodship5, Reference Driscoll, Budarf and Emanual6
Conotruncal anomaly face syndrome had first been reported in 1976.Reference Kinouchi, Mori, Ando and Takao7 In the early 1970s, Atsuyoshi Takao had begun to recognize a characteristic facial appearance, with a flat nasal bridge, a small mouth, a nasal voice, a high arched palate, abnormalities of the ear lobes, and mental retardation among patients with abnormalities of the ventricular outflow tracts, mostly tetralogy of Fallot. He named this combination “conotruncal anomaly face syndrome”. He was able to make the diagnosis simply by observing the face and listening to the voice of a patient, and sometimes the patient’s mother. When I first came to Tokyo Women’s Medical University as a fellow in 1976, the concept of the conotruncal anomaly face syndrome had already been established in the Heart Institute of Japan. Atsuyoshi asked Akiko Kinouchi to write a paper about the syndrome, and in 1976 she wrote a paper in Japanese.Reference Kinouchi, Mori, Ando and Takao7 This paper was the first to describe conotruncal anomaly face syndrome. In those days, I did not imagine that a chromosomal abnormality could be identified in this syndrome. It was only several years later that Atsuyoshi told Rumiko Matsuoka, who was working with Richard Van Praagh, to study molecular biology in Boston. Later, he said that all the purposes of establishing our laboratory for molecular biology were to investigate the aetiology of conotruncal anomaly face syndrome.
Be that as it may, in the mid 1970s, Dr Takao wanted to evaluate the characteristics of the face and fingerprints of this syndrome. Akiko Kinouchi measured the length of various parts of the face in patients with this syndrome, and she published further papers in 1980.Reference Kinouchi8, Reference Takao, Ando, Cho, Kinouchi, Murakami, Takao and Van Praagh9 In those days, cardiac surgeons already had noted that some patients with the syndrome did not have a thymus. Recognizing that the syndrome shared some common phenotypes with DiGeorge syndrome, around 1980 Dr Takao and his fellow Takashi Shimizu studied immunodeficiency in patients with the syndrome.Reference Shimizu, Takao, Ando, Hirayama, Nora and Takao10 The results showed that the population of T cells was subnormal in four-fifths of patients with the syndrome, but a decreased T cell count was noted in only 7%. In twothirds of patients, however, they also found a poor response to the phytohemagglutinin skin test, an indicator of a T-cell mediated immune response. Atsuyoshi Takao also noted a high frequency of anomalies of the aortic arch, such as cervical aortic and abnormal origin of the subclavian artery, in these patients, and these results were published in 1985.Reference Terai, Takao and Ando11 Later, after confirmation of chromosome 22q11 deletion, Kazuo Momma reviewed cardiovascular abnormalities in the syndrome, by then known appropriately as Takao syndrome.Reference Momma, Kondo, Matsuoka and Takao12
Velo-cardio-facial syndrome, or Shprintzen syndrome
In 1978, Shprintzen and colleaguesReference Shprintzen, Goldberg and Lewin13 published a paper about patients with a cleft palate, cardiac anomalies, typical facies, and learning disabilities, which they called the velo-cardio-facial syndrome. After reading their paper, Atsuyoshi sent a letter to Shprintzen suggesting that conotruncal anomaly face syndrome and velo-cardio-facial syndrome might be the same entity. In reply, Dr Shprintzen asked if he could see patients with conotruncal anomaly face syndrome, but somehow, there was no chance for him to see the patients. There was also no chance for them to meet each other. In 1992, however, velo-cardio-facial syndrome was found to be associated with microdeletion of chromosome 22q11,Reference Scambler, Kelly and Lindsay14 while in 1993, similar deletion was confirmed in conotruncal anomaly face syndrome.Reference Burn, Takao and Wilson15, Reference Burn, Wilson, Cross, Clark, Markwald and Takao16 Throughout his life, nonetheless, Atsuyoshi never claimed that he was the first to have described this syndrome.
Kawasaki disease
The mucocutaneous lymph node syndrome, or Kawasaki disease, was first reported by Kawasaki in 1967. Atsuyoshi Takao once saw a patient with severe mitral regurgitation. When he looked at a chest X-ray carefully, he noted a calcification at an unusual site in the cardiac silhouette. He thought that the calcification might be in the wall of a coronary artery, and that the mitral regurgitation might have been due to the coronary arterial calcification associated with Kawasaki disease.Reference Hamada, Takao and Mimori17 He was the first to emphasize the importance of aortography or coronary angiography in Kawasaki disease.Reference Takao, Kusakawa, Hamada, Ando and Asai18 Now, Kawasaki disease is well established as a cause of mitral regurgitation in children.Reference Takao, Niwa, Kondoh and Shulman19
Basic science in the 1970s and 1980s
Dr Takao was very interested in the research of cardiac morphogenesis. In the 1970s, he wanted to produce cardiac anomalies to clarify the mechanisms of congenital cardiac disease. In the early 1970s, together with Shizen Ishikawa, he noted that the frequencies of ventricular septal defect and anomalies of the aortic arch were high in chick embryos after centrifugation.Reference Ishikawa, Takao, Ando and Mori20 In the late1970s, he instructed his fellows to study the effect of radiation and electric shock on cardiac development.Reference Ishikawa, Nagao and Okawa21, Reference Kawamura, Takao, Ando, Takao and Van Praagh22 In the early 1980s, he told his fellows to study the effect of various drugs, such as a retinoic acid, bisdiamine, and nimustin.Reference Zen I Ando and Takao23, Reference Zen, Ando and Takao24 They found that maternal administration of a retinoic acid caused heterotaxy syndrome and transposed great arteries in the mouse.Reference Irie, Ando and Yakao25–Reference Yasui, Nakazawa, Morishima, Ando, Takao and Aikawa27 They also found thymic abnormalities and interruption of the aortic arch between the left common carotid and left subclavian arteries. Despite these experiments, Dr Takao began to feel a limitation of methodology in experimental teratology to clarify the mechanism of the malformed heart.
The Takao meeting
To resolve these inadequacies, Dr Takao determined to hold an international conference to stimulate and integrate research on the morphogenesis of the heart. The Sankei Takao symposium was first held in 1978, with the financial support of The Sankei Newspaper, and donations from ex-fellows of the Department of Pediatric Cardiology at the Heart Institute of Japan. Dr Takao did not want to use his name as the title of the symposium. and the conference was called “Symposium on the Etiology and Morphogenesis of Congenital Heart Disease” (Fig. 8). Dr Takao also did not like to receive donations from pharmaceutical companies, as he thought such donations could possibly involve a conflict of interest. A book was published after each symposium, appearing in 1980, 1984, 1990, 1995, and 2000.Reference Van Praagh and Takao28–Reference Clark, Nakazawa and Takao32 The co-editors were Richard Van Praagh, James Nora, Roger Markwald, Edward Clark, and Makoto Nakazawa.
The Takao meeting in 1993. Front, from left, Kenneth Chien, Julie Korenberg, Ed Clark, Atsuyoshi Takao, Roger Markwald, Charlotte Ferencz, John Burn. Behind Ed Clark, Kazuo Momma, and Brad Keller.
Molecular biology
Dr Takao realized the importance of molecular biology in the late 1970s. After Atsuyoshi retired in 1990, he began to study molecular biology himself, striving hard to learn the various techniques. Although he did not perform experiments himself, he became a good molecular biologist. In 1990, he set up the International Molecular Cellular Immunological Research Center. He worked as a director of the Institute until 2006. In 2003, investigators of the Institute, including Atsuyoshi Takao and Rumiko Matsuoka, published a paper suggesting that mutation of the TBX1 gene was responsible for conotruncal anomaly face syndrome.Reference Yagi, Furutani and Hamada33
Thanatology
Dr Takao also studied hard with regard to thanatology. In the textbook of pediatric cardiology “Clinical Developmental Cardiology”, he wrote a chapter on thanatology, placing the poem shown above at the top of the chapter.Reference Takao, Momma, Nakazawa and Nakanishi34 In the text, he emphasized the importance of thanatology in pediatric cardiology and said, “The art of dying is the art of living”, “We can live just because we die” and “Pediatric cardiology should become longitudinal cardiology if we look at patients with congenital heart disease from the point of view of thanatology”. I sometimes wonder what the death of patients with congenitally malformed hearts meant to him? Upon the death of patients, Atsuyoshi showed a deep sympathy to the parents, and they thanked him. He showed me the importance of sharing the notion of thanatology with the families of the patients.
Conclusion
Atsuyoshi Takao was a father of paediatric cardiology in Japan. He showed me the way to live, and was my life-long mentor. Many cardiac fellows admired him, loved him, and felt like he was a father to them. He will continue to live on in our memory.
