Association of Severity of Coronary Artery Aneurysms in Patients With Kawasaki Disease and Risk of Later Coronary Events

Masaru Miura; Tohru Kobayashi; Tetsuji Kaneko; Mamoru Ayusawa; Ryuji Fukazawa; Naoya Fukushima; Shigeto Fuse; Kenji Hamaoka; Keiichi Hirono; Taichi Kato; Yoshihide Mitani; Seiichi Sato; Shinya Shimoyama; Junko Shiono; Kenji Suda; Hiroshi Suzuki; Jun Maeda; Kenji Waki; and The Z-score Project 2nd Stage Study Group; Hitoshi Kato; Tsutomu Saji; Hiroyuki Yamagishi; Aya Ozeki; Masako Tomotsune; Makiko Yoshida; Yohei Akazawa; Kentaro Aso; Shouzaburoh Doi; Yoshi Fukasawa; Kenji Furuno; Yasunobu Hayabuchi; Miyuki Hayashi; Takafumi Honda; Norihisa Horita; Kazuyuki Ikeda; Masahiro Ishii; Satoru Iwashima; Masahiro Kamada; Masahide Kaneko; Hiroshi Katyama; Yoichi Kawamura; Atushi Kitagawa; Akiko Komori; Kenji Kuraishi; Hiroshi Masuda; Shinichi Matsuda; Satoshi Matsuzaki; Sayaka Mii; Tomoyuki Miyamoto; Yuji Moritou; Noriko Motoki; Kiyoshi Nagumo; Tsuneyuki Nakamura; Eiki Nishihara; Yuichi Nomura; Shohei Ogata; Hiroyuki Ohashi; Kenichi Okumura; Daisuke Omori; Tetsuya Sano; Eisuke Suganuma; Tsutomu Takahashi; Shinichi Takatsuki; Atsuhito Takeda; Masaru Terai; Manatomo Toyono; Kenichi Watanabe; Makoto Watanabe; Masaki Yamamoto; Kenichiro Yamamura

doi:10.1001/jamapediatrics.2018.0030

. 2018 Mar 5;172(5):e180030. doi: 10.1001/jamapediatrics.2018.0030

Association of Severity of Coronary Artery Aneurysms in Patients With Kawasaki Disease and Risk of Later Coronary Events

Masaru Miura ^1,^2,^✉, Tohru Kobayashi ³, Tetsuji Kaneko ², Mamoru Ayusawa ⁴, Ryuji Fukazawa ⁵, Naoya Fukushima ¹, Shigeto Fuse ⁶, Kenji Hamaoka ⁷, Keiichi Hirono ⁸, Taichi Kato ⁹, Yoshihide Mitani ¹⁰, Seiichi Sato ¹¹, Shinya Shimoyama ¹², Junko Shiono ¹³, Kenji Suda ¹⁴, Hiroshi Suzuki ¹⁵, Jun Maeda ¹⁶, Kenji Waki ¹⁷; and The Z-score Project 2nd Stage Study Group, Hitoshi Kato ³, Tsutomu Saji ¹⁸, Hiroyuki Yamagishi ¹⁶, Aya Ozeki ², Masako Tomotsune ², Makiko Yoshida ², Yohei Akazawa ¹⁹, Kentaro Aso ²⁰, Shouzaburoh Doi ²¹, Yoshi Fukasawa ⁹, Kenji Furuno ²², Yasunobu Hayabuchi ²³, Miyuki Hayashi ⁵, Takafumi Honda ²⁴, Norihisa Horita ²⁵, Kazuyuki Ikeda ⁷, Masahiro Ishii ²⁶, Satoru Iwashima ²⁷, Masahiro Kamada ²⁸, Masahide Kaneko ³, Hiroshi Katyama ²⁹, Yoichi Kawamura ³⁰, Atushi Kitagawa ²⁶, Akiko Komori ⁴, Kenji Kuraishi ³¹, Hiroshi Masuda ³, Shinichi Matsuda ³², Satoshi Matsuzaki ¹⁹, Sayaka Mii ³³, Tomoyuki Miyamoto ³⁴, Yuji Moritou ²⁸, Noriko Motoki ¹⁹, Kiyoshi Nagumo ³⁵, Tsuneyuki Nakamura ³⁶, Eiki Nishihara ³¹, Yuichi Nomura ³⁷, Shohei Ogata ²⁶, Hiroyuki Ohashi ¹⁰, Kenichi Okumura ²⁹, Daisuke Omori ³⁸, Tetsuya Sano ³⁹, Eisuke Suganuma ³², Tsutomu Takahashi ⁴⁰, Shinichi Takatsuki ¹⁸, Atsuhito Takeda ⁴¹, Masaru Terai ²⁴, Manatomo Toyono ⁴², Kenichi Watanabe ¹⁵, Makoto Watanabe ⁵, Masaki Yamamoto ⁴³, Kenichiro Yamamura ⁴⁴

¹Department of Cardiology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan

²Clinical Research Support Center, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan

³Division of Clinical Research Planning, Department of Development Strategy, Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan

⁴Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan

⁵Department of Pediatrics, Nippon Medical School, Tokyo, Japan

⁶Department of Pediatrics, NTT Sapporo Medical Center, Hokkaido, Japan

⁷Department of Pediatric Cardiology and Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

⁸Department of Pediatrics, Graduate School of Medicine, University of Toyama, Toyama, Japan

⁹Division of Clinical Research Planning, Department of Development Strategy, Center for Department of Pediatrics, Nagoya University Hospital, Aichi, Japan

¹⁰Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan

¹¹Department of Pediatrics, Niigata City General Hospital, Niigata, Japan

¹²Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan

¹³Department of Pediatric Cardiology, Ibaraki Children's Hospital, Ibaraki, Japan

¹⁴Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan

¹⁵Department of Pediatrics, Niigata University, Niigata, Japan

¹⁶Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan

¹⁷Department of Pediatrics, Kurashiki Central Hospital, Okayama, Japan

¹⁸Department of Pediatrics, Toho University Medical Center Omori Hospital, Tokyo, Japan

¹⁹Department of Pediatrics, Shinshu University School of Medicine, Nagano, Japan

²⁰Department of Pediatrics, St. Marianna University School of Medicine, Kanagawa, Japan

²¹Department of Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan

²²Department of General Pediatrics & Interdisciplinary Medicine, Fukuoka Children's Hospital, Fukuoka, Japan

²³Department of Pediatrics, Tokushima University, Tokushima, Japan

²⁴Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Chiba, Japan

²⁵Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan

²⁶Department of Pediatrics, Kitasato University, Kanagawa, Japan

²⁷Department of Pediatrics, Hamamatsu University School of Medicine, Shizuoka, Japan

²⁸Department of Pediatrics, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan

²⁹Department of Pediatrics, Osaka Medical College, Osaka, Japan

³⁰Department of Pediatrics, National Defense Medical College, Saitama, Japan

³¹Department of Pediatric Cardiology and Neonatology, Ogaki Municipal Hospital, Gifu, Japan

³²Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan

³³Department of Pediatrics, Japanese Red Cross Nagoya Daiichi Hospital, Aichi, Japan

³⁴Department of Pediatrics, Yokosuka General Hospital Uwamachi, Kanagawa, Japan

³⁵Department of Pediatrics, Teine Keijinkai Hospital, Hokkaido, Japan

³⁶Department of Pediatrics, Kanazawa Medical University, Ishikawa, Japan

³⁷Department of Pediatrics, Kagoshima University, Kagoshima, Japan

³⁸Japan Community Healthcare Organization Chukyo Hospital, Nagoya, Japan

³⁹Department of Pediatrics, Japan Community Healthcare Organization Osaka Hospital, Osaka, Japan

⁴⁰Department of Pediatrics, Saiseikai Utsunomiya Hospital, Tochigi, Japan

⁴¹Department of Pediatrics, Hokkaido University Hospital, Hokkaido, Japan

⁴²Department of Pediatrics, Akita University, Akita, Japan

⁴³Department of Pediatrics, Kochi University, Kochi, Japan

⁴⁴Department of Pediatrics, Kyushu University, Fukuoka, Japan

Group Information: The Z-score Project 2nd Stage Study Group authors and members are listed at the end of the article.

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Corresponding Author: Masaru Miura, MD, PhD, Department of Cardiology, Tokyo Metropolitan Children's Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo 183-8561, Japan (masaru10miura@gmail.com).

Accepted for Publication: January 2, 2018.

Published Online: March 5, 2018. doi:10.1001/jamapediatrics.2018.0030

The Z-score Project 2nd Stage Authors: The following investigators take authorship responsibility for the study results: Hitoshi Kato, MD, PhD; Tsutomu Saji, MD, PhD; Hiroyuki Yamagishi, MD, PhD; Aya Ozeki, MSc; Masako Tomotsune, BN; Makiko Yoshida, BPhrm; Yohei Akazawa, MD, PhD; Kentaro Aso, MD, PhD; Shouzaburoh Doi, MD, PhD; Yoshi Fukasawa, MD; Kenji Furuno, MD, PhD; Yasunobu Hayabuchi, MD, PhD; Miyuki Hayashi, MD, PhD; Takafumi Honda, MD; Norihisa Horita, MD, PhD; Kazuyuki Ikeda, MD, PhD; Masahiro Ishii, MD, PhD; Satoru Iwashima, MD, PhD; Masahiro Kamada, MD, PhD; Masahide Kaneko, MD; Hiroshi Katyama, MD, PhD; Yoichi Kawamura, MD, PhD; Atushi Kitagawa, MD, PhD; Akiko Komori, MD; Kenji Kuraishi, MD; Hiroshi Masuda, MD; Shinichi Matsuda, MD; Satoshi Matsuzaki, MD, PhD; Sayaka Mii, MD; Tomoyuki Miyamoto, MD; Yuji Moritou, MD; Noriko Motoki, MD, PhD; Kiyoshi Nagumo, MD, PhD; Tsuneyuki Nakamura, MD; Eiki Nishihara, MD; Yuichi Nomura, MD, PhD; Shohei Ogata, MD, PhD; Hiroyuki Ohashi, MD; Kenichi Okumura, MD, PhD; Daisuke Omori, MD; Tetsuya Sano, MD; Eisuke Suganuma, MD, PhD; Tsutomu Takahashi, MD, PhD; Shinichi Takatsuki, MD; Atsuhito Takeda, MD, PhD; Masaru Terai, MD, PhD; Manatomo Toyono, MD, PhD; Kenichi Watanabe, MD, PhD; Makoto Watanabe, MD; Masaki Yamamoto, MD; Kenichiro Yamamura, MD, PhD.

Affiliations of The Z-score Project 2nd Stage Authors: Clinical Research Support Center, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan (Ozeki, Tomotsune, Yoshida); Division of Clinical Research Planning, Department of Development Strategy, Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan (Kato, Kaneko, Masuda); Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (Komori); Department of Pediatrics, Nippon Medical School, Tokyo, Japan (Hayashi, M. Watanabe); Department of Pediatric Cardiology and Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (Ikeda); Division of Clinical Research Planning, Department of Development Strategy, Center for Department of Pediatrics, Nagoya University Hospital, Aichi, Japan (Fukasawa); Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan (Ohashi); Department of Pediatrics, Niigata University, Niigata, Japan (K. Watanabe); Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan (Yamagishi); Department of Pediatrics, Toho University Medical Center Omori Hospital, Tokyo, Japan (Saji, Takatsuki); Department of Pediatrics, Shinshu University School of Medicine, Nagano, Japan (Akazawa, Matsuzaki, Motoki); Department of Pediatrics, St. Marianna University School of Medicine, Kanagawa, Japan (Aso); Department of Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan (Doi); Department of General Pediatrics & Interdisciplinary Medicine, Fukuoka Children's Hospital, Fukuoka, Japan (Furuno); Department of Pediatrics, Tokushima University, Tokushima, Japan (Hayabuchi); Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Chiba, Japan (Honda, Terai); Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan (Horita); Department of Pediatrics, Kitasato University, Kanagawa, Japan (Ishii, Kitagawa, Ogata); Department of Pediatrics, Hamamatsu University School of Medicine, Shizuoka, Japan (Iwashima); Department of Pediatrics, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan (Kamada, Moritou); Department of Pediatrics, Osaka Medical College, Osaka, Japan (Katyama, Okumura); Department of Pediatrics, National Defense Medical College, Saitama, Japan (Kawamura); Department of Pediatric Cardiology and Neonatology, Ogaki Municipal Hospital, Gifu, Japan (Kuraishi, Nishihara); Department of Pediatrics, Tokai University School of Medicine, Kanagawa, Japan (Matsuda, Suganuma); Department of Pediatrics, Japanese Red Cross Nagoya Daiichi Hospital, Aichi, Japan (Mii); Department of Pediatrics, Yokosuka General Hospital Uwamachi, Kanagawa, Japan (Miyamoto); Department of Pediatrics, Teine Keijinkai Hospital, Hokkaido, Japan (Nagumo); Department of Pediatrics, Kanazawa Medical University, Ishikawa, Japan (Nakamura); Department of Pediatrics, Kagoshima University, Kagoshima, Japan (Nomura); Japan Community Healthcare Organization Chukyo Hospital, Nagoya, Japan (Omori); Department of Pediatrics, Japan Community Healthcare Organization Osaka Hospital, Osaka, Japan (Sano); Department of Pediatrics, Saiseikai Utsunomiya Hospital, Tochigi, Japan (Takahashi); Department of Pediatrics, Hokkaido University Hospital, Hokkaido, Japan (Takeda); Department of Pediatrics, Akita University, Akita, Japan (Toyono); Department of Pediatrics, Kochi University, Kochi, Japan (Yamamoto); Department of Pediatrics, Kyushu University, Fukuoka, Japan (Yamamura).

Author Contributions: Dr Miura had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Miura, Kobayashi, Hamaoka, T. Kato, Waki, Saji, Doi.

Acquisition, analysis, or interpretation of data: Miura, Kobayashi, T. Kaneko, Ayusawa, Fukazawa, Fukushima, Fuse, Hamaoka, Hirono, T. Kato, Mitani, Sato, Shimoyama, Shiono, Suda, Suzuki, Maeda, Waki, H. Kato, Yamagishi, Ozeki, Tomotsune, Yoshida, Akazawa, Aso, Fukasawa, Furuno, Hayabuchi, Hayashi, Honda, Horita, Ikeda, Ishii, Iwashima, Kamada, M. Kaneko, Katayama, Kawamura, Kitagawa, Komori, Kuraishi, Masuda, Matsuda, Matsuzaki, Mii, Miyamoto, Moritou, Motoki, Nagumo, Nakamura, Nishihara, Nomura, Ogata, Ohashi, Okumura, Omori, Sano, Suganuma, Takahashi, Takatsuki, Takeda, Terai, Toyono, K. Watanabe, M. Watanabe, Yamamoto, Yamamura.

Drafting of the manuscript: Miura, Fukushima, Hamaoka, Hirono, Doi, Ikeda, Ishii, Iwashima, Nagumo, K. Watanabe.

Critical revision of the manuscript for important intellectual content: Kobayashi, T. Kaneko, Ayusawa, Fukazawa, Fuse, Hamaoka, T. Kato, Mitani, Sato, Shimoyama, Shiono, Suda, Suzuki, Maeda, Waki, H. Kato, Saji, Yamagishi, Ozeki, Tomotsune, Yoshida, Akazawa, Aso, Fukasawa, Furuno, Hayabuchi, Hayashi, Honda, Horita, Kamada, M. Kaneko, Katayama, Kawamura, Kitagawa, Komori, Kuraishi, Masuda, Matsuda, Matsuzaki, Mii, Miyamoto, Moritou, Motoki, Nakamura, Nishihara, Nomura, Ogata, Ohashi, Okumura, Omori, Sano, Suganuma, Takahashi, Takatsuki, Takeda, Terai, Toyono, M. Watanabe, Yamamoto, Yamamura.

Statistical analysis: Miura, Kobayashi, T. Kaneko, Ozeki.

Obtained funding: Miura, Ayusawa, Sato, Mii.

Administrative, technical, or material support: T. Kaneko, Fukazawa, Fuse, Hamaoka, Hirono, T. Kato, Mitani, Shimoyama, Suzuki, Waki, H. Kato, Saji, Yamagishi, Ozeki, Tomotsune, Yoshida, Akazawa, Aso, Fukasawa, Furuno, Hayabuchi, Honda, Horita, Ishii, Iwashima, Kamada, M. Kaneko, Katayama, Kawamura, Kitagawa, Komori, Kuraishi, Masuda, Matsuda, Miyamoto, Nakamura, Nishihara, Ogata, Okumura, Omori, Sano, Suganuma, Takahashi, Takatsuki, Takeda, Terai, M. Watanabe, Yamamoto, Yamamura.

Study supervision:Kobayashi, Fukazawa, Hamaoka, Suda, Maeda, Saji, Yamagishi, Matsuzaki, Nomura.

Conflict of Interest Disclosures: Drs Miura, Kobayashi, Ayusawa, and Fuse received an honorarium from the Japan Blood Products Organization and Teijin Pharma Limited Nihon Pharmaceutical Co. Drs Miura, Kobayashi, Kato, and Ayusawa received an honorarium from the Mitsubishi Tanabe Pharma Corporation. No other disclosures are reported.

Funding/Support: This study was supported by grants from Clinical Research for Tokyo Metropolitan Hospitals and the Kawasaki Disease Research Center.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

The Z-score Project 2nd Stage Study Group: Steering committee: Masaru Miura, MD, PhD, Tokyo Metropolitan Children’s Medical Center, Ryuji Fukazawa, MD, PhD, Nippon Medical School, Shigeto Fuse, MD, PhD, NTT Sapporo Medical Center, Kenji Hamaoka, MD, PhD, Kyoto Prefectural University of Medicine, Keiichi Hirono, MD, PhD, University of Toyama, Hitoshi Kato, MD, PhD, National Center for Child Health and Development, Taichi Kato, MD, PhD, Nagoya University Hospital, Tohru Kobayashi, MD, PhD, National Center for Child Health and Development, Tsutomu Saji, MD, PhD, Toho University Medical Center Omori Hospital, Kenji Suda, MD, PhD, Kurume University, Kenji Waki, MD, PhD, Kurashiki Central Hospital, and Hiroyuki Yamagishi, MD, PhD, Keio University. Study office: Naoya Fukushima, MD, Tokyo Metropolitan Children’s Medical Center. Data coordination center: Tetsuji Kaneko, MSc, Aya Ozeki, MSc, Masako Tomotsune, BN, and Makiko Yoshida, BPhrm (all Tokyo Metropolitan Children’s Medical Center). Clinical investigators: Yohei Akazawa, MD, PhD, Shinshu University, Kentaro Aso, MD, PhD, St Marianna University, Mamoru Ayusawa, MD, PhD, Nihon University, Shozaburo Doi, MD, PhD, Tokyo Medical and Dental University, Yoshie Fukasawa, MD, Nagoya University Hospital, Kenji Furuno, MD, PhD, Fukuoka Children’s Hospital, Yasunobu Hayabuchi, MD, PhD, Tokushima University, Miyuki Hayashi, MD, PhD, Nippon Medical School, Takafumi Honda, MD, Tokyo Women’s Medical University Yachiyo Medical Center, Norihisa Horita, MD, PhD, Sapporo Medical University, Kazuyuki Ikeda, MD, PhD, Kyoto Prefectural University of Medicine, Masahiro Ishii, MD, PhD, Kitasato University, Satoru Iwashima, MD, PhD, Hamamatsu University, Masahiro Kamada, MD, PhD, Hiroshima City Hiroshima Citizens Hospital, Masahide Kaneko, MD, National Center for Child Health and Development, Hiroshi Katayama, MD, PhD, Osaka Medical College, Yoichi Kawamura, MD, PhD, National Defense Medical College, Atushi Kitagawa, MD, PhD, Kitasato University, Akiko Komori, MD, Nihon University, Kenji Kuraishi, MD, Ogaki Municipal Hospital, Jun Maeda, MD, PhD, Keio University, Hiroshi Masuda, MD, National Center for Child Health and Development, Shinichi Matsuda, MD, Tokai University, Satoshi Matsuzaki, MD, PhD, Shinshu University, Sayaka Mii, MD, Japanese Red Cross Nagoya Daiichi Hospital, Yoshihide Mitani, MD, PhD, Mie University, Tomoyuki Miyamoto, MD, Yokosuka General Hospital Uwamachi, Yuji Moritou, MD, Hiroshima City Hiroshima Citizens Hospital, Noriko Motoki, MD, PhD, Shinshu University, Kiyoshi Nagumo, MD, PhD, Teine Keijinkai Hospital, Tsuneyuki Nakamura, MD, Kanazawa University; Eiki Nishihara, MD, Ogaki Municipal Hospital, Yuichi Nomura, MD, PhD, Kagoshima University, Shohei Ogata, MD, PhD, Kitasato University, Hiroyuki Ohashi, MD, Mie University, Kenichi Okumura, MD, PhD, Osaka Medical College, Daisuke Omori, MD, Japan Community Healthcare Organization Chukyo Hospital, Tetsuya Sano, MD, Japan Community Healthcare Organization Osaka Hospital, Seiichi Sato, MD, PhD, Niigata City General Hospital, Shinya Shimoyama, MD, PhD, Gunma University, Junko Shiono, MD, PhD, Ibaraki Children’s Hospital, Eisuke Suganuma, MD, PhD, Tokai University, Hiroshi Suzuki, MD, PhD, Niigata University, Tsutomu Takahashi, MD, PhD, Saisikai Utsunomiya Hospital, Shinichi Takatsuki, MD, Toho University Medical Center Omori Hospital, Atsuhito Takeda, MD, PhD, Hokkaido University Hospital, Masaru Terai, MD, PhD, Tokyo Women’s Medical University Yachiyo Medical Center, Manatomo Toyono, MD, PhD, Akita University, Kenichi Watanabe, MD, PhD, Niigata University, Makoto Watanabe, MD, Nippon Medical School; Masaki Yamamoto, MD, Kochi University, and Kenichiro Yamamura, MD, PhD, Kyushu University. Institutions (number of patients contributed): Akita University (20), Fukuoka Children's Hospital (17), Gunma Children's Medical Center (59), Gunmaken Saiseikai Maebashi Hospital (46), Hamamatsu University School of Medicine (20), Hiroshima City Hiroshima Citizens Hospital (3), Hokkaido University Hospital (10), Ibaraki Children's Hospital (41), Japan Community Healthcare Organization Chukyo Hospital (17), Japan Community Healthcare Organization Osaka Hospital (2), Japanese Red Cross Nagoya Daiichi Hospital (48), Kagoshima University (11), Kanazawa Medical University (1), Keio University Hospital (78), Kitasato University (16), Kochi University (5), Kurashiki Central Hospital (30), Kurume University (102), Kyoto Prefectural University of Medicine (40), Kyushu University (10), Mie University (31), Nagoya University Hospital (4), National Center for Child Health and Development (13), National Defense Medical College (2), Niigata City General Hospital (40), Niigata University (35), Nippon Medical School (22), NTT Sapporo Medical Center (5), Ogaki Municipal Hospital (7), Osaka Medical College (16), Saiseikai Utsunomiya Hospital (16), Sapporo Medical University (18), Shinshu University School of Medicine, (10), St. Marianna University School of Medicine (7), Teine Keijinkai Hospital (3), Toho University Medical Center Omori Hospital (4), Tokai University (2), Tokushima University (7), Tokyo Medical and Dental University (1), Tokyo Metropolitan Children's Medical Center (125), Tokyo Women's Medical University Yachiyo Medical Center (5), University of Toyama (41), and Yokosuka General Hospital Uwamachi (6).

Additional Contributions: We thank Yosikazu Nakamura, MD, Jichi Medical University, for providing the data on the Kawasaki disease nationwide survey, Tohru Itoi, SORA Design Office, for his management of the website, and the in-house editor James R. Valera, Tokyo Metropolitan Government, for his assistance in editing and proofreading the manuscript. We offer our condolences to the family of Tsutomu Saji, MD, Toho University Medical Center, the supervisor of this study, who passed away on May 22, 2017. Mr Itoi and Mr Valera were compensated for their contributions.

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Corresponding author.

PMCID: PMC5875323 PMID: 29507955

Key Points

Questions

Is the internal diameter z score associated with time-dependent coronary events in patients with Kawasaki disease with coronary artery aneurysms?

Findings

This cohort study surveyed 1006 patients with Kawasaki disease younger than 19 years who received a coronary angiography and found that the 10-year event-free survival rate for coronary events was 100%, 94%, and 52% in men and 100%, 100%, and 75% in women for small, medium, and large aneurysms, respectively. Large aneurysms, male sex, and resistance to intravenous immunoglobulin therapy were associated with coronary events.

Meaning

Careful management is essential for men and treatment-resistant patients with large coronary artery aneurysms based on the internal diameter z score.

Abstract

Importance

Few studies with sufficient statistical power have shown the association of the z score of the coronary arterial internal diameter with coronary events (CE) in patients with Kawasaki disease (KD) with coronary artery aneurysms (CAA).

Objective

To clarify the association of the z score with time-dependent CE occurrence in patients with KD with CAA.

Design, Setting, and Participants

This multicenter, collaborative retrospective cohort study of 44 participating institutions included 1006 patients with KD younger than 19 years who received a coronary angiography between 1992 and 2011.

Main Outcomes and Measures

The time-dependent occurrence of CE, including thrombosis, stenosis, obstruction, acute ischemic events, and coronary interventions, was analyzed for small (z score, <5), medium (z score, ≥5 to <10; actual internal diameter, <8 mm), and large (z score, ≥10 or ≥8 mm) CAA by the Kaplan-Meier method. The Cox proportional hazard regression model was used to identify risk factors for CE after adjusting for age, sex, size, morphology, number of CAA, resistance to initial intravenous immunoglobulin (IVIG) therapy, and antithrombotic medications.

Results

Of 1006 patients, 714 (71%) were male, 341 (34%) received a diagnosis before age 1 year, 501 (50%) received a diagnosis between age 1 and 5 years, and 157 (16%) received a diagnosis at age 5 years or older. The 10-year event-free survival rate for CE was 100%, 94%, and 52% in men (P < .001) and 100%, 100%, and 75% in women (P < .001) for small, medium, and large CAA, respectively. The CE-free rate was 100%, 96%, and 79% in patients who were not resistant to IVIG therapy (P < .001) and 100%, 96%, and 51% in patients who were resistant to IVIG therapy (P < .001), respectively. Cox regression analysis revealed that large CAA (hazard ratio, 8.9; 95% CI, 5.1–15.4), male sex (hazard ratio, 2.8; 95% CI, 1.7–4.8), and resistance to IVIG therapy (hazard ratio, 2.2; 95% CI, 1.4–3.6) were significantly associated with CE.

Conclusions and Relevance

Classification using the internal diameter z score is useful for assessing the severity of CAA in relation to the time-dependent occurrence of CE and associated factors in patients with KD. Careful management of CE is necessary for all patients with KD with CAA, especially men and IVIG-resistant patients with a large CAA.

This study demonstrates the use of the z score of the coronary arterial internal diameter for classifying the severity of coronary artery aneurysms in association with the occurrence of coronary events and major adverse cardiac events in patients with Kawasaki disease.

Introduction

In developed countries, Kawasaki disease (KD) is the most common cause of pediatric acquired heart disease with coronary artery aneurysms (CAA). Patients with KD with a large CAA often experience coronary events (CE), such as thrombosis, stenosis, and obstruction, leading to major adverse cardiac events (MACE), such as unstable angina pectoris or myocardial infarction and even death. Antithrombotic medical treatments and cardiac interventions are performed to prevent or treat these acute ischemic events.

The actual internal diameter of the CAA has been used in clinical management to predict CE,^1,2 but the conventional criteria are flawed because of the lack of adjustment for body size and may lead to the underdiagnosis of the severity of CAA,^3,4 especially in younger individuals. Several groups^5,6,7 have proposed equations to calculate the z score of the coronary arterial internal diameter adjusted for body surface area. Thus, the current guidelines of the American Heart Association⁴ have adopted a new classification based on the z score; however, to our knowledge there are few studies with sufficient statistical power to provide a reliable account of the association between CE and severity classification based on the z score of the internal diameter. In a recent report, Friedman et al⁸ found the incidence of these events, including complete occlusion, myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention, cardiac death, ventricular tachycardia, and orthotopic heart transplant, to be high and the regression rate to be low in 90 cases of large CAA as measured by the z score of the internal diameter, whereas the number of patients with MACE was comparatively small at 24. In addition, it is unclear whether the occurrence of CE is related to other factors, such as age, sex, morphology of CAA, severity in the acute phase, and medical interventions. The aim of this study was to clarify the association of the z score of the coronary arterial internal diameter with the time-dependent occurrence of CE and other related factors in patients with KD with CAA using a large-scale cohort in Japan.

Methods

Study Design

We performed a retrospective medical record review in a multicenter cohort study conducted in Japan with 44 participating institutions from July 2012 to December 2015. Patients with consecutive KD (age <19 years) who received a coronary angiography, including cardiac catheterization, coronary multidetector computed tomography, or magnetic resonance coronary angiography, between January 1992 and December 2011 were included. Patients were excluded if the coronary arterial internal diameter had not been determined by echocardiography in the acute phase or if other severe disorders affecting the coronary artery lesions or prognosis, such as familial hypercholesterolemia, cardiomyopathy, or severe congenital heart disease, were present. At each institute, patients with KD were examined and treated based on the guidelines of the Japanese Society of Cardiology¹ and the Japanese Society of Pediatric Cardiology and Cardiac Surgery.⁹ Because this was a retrospective observational study, informed consent was waived based on the judgment of the central ethics board at Tokyo Metropolitan Children’s Medical Center.

This study was conducted in accordance with the principles of the Declaration of Helsinki and the ethical guidelines issued by the Ministry of Health, Labour, and Welfare, Japan, and was approved by a central ethics board at Tokyo Metropolitan Children’s Medical Center (approval number, H23–105). This study has been registered with the University Hospital Medical Information Network clinical trials registry (UMIN000010606).

Variables

We longitudinally studied patient data on demographics, medical interventions, coronary arterial internal diameter and morphology, cardiac interventions, and cardiac outcomes from the time of the first diagnosis to the last visit. Demographic data included sex, age at KD diagnosis, weight and height at the time of KD diagnosis, the date of the last visit, and mortality. Age at KD diagnosis was divided into 3 categories: (1) younger than 1 year, (2) 1 to 4 years, and (3) 5 years or older. Medical interventions included anti-inflammatory treatments (intravenous immunoglobulin [IVIG], prednisolone or pulsed methylprednisolone, ulinastatin, infliximab, cyclosporine, or plasma exchange) during the acute phase, antiplatelet medicines in the acute or chronic phase, and warfarin treatment during the chronic phase. We did not collect data on the dosage or use of medications. The acute phase was defined as occurring within 90 days of illness onset, and the chronic phase was defined as a period of illness lasting 91 days or longer. A patient who required any treatment following the initial IVIG treatment was considered to have been resistant to the initial IVIG treatment.

We collected data on the maximum coronary arterial internal diameter of the right coronary artery, left main coronary artery, left anterior descending artery, and left circumflex coronary artery by echocardiography during the acute phase. Echocardiographic studies were done 3 times or more within 2 weeks after diagnosis. The configuration and number of CAA were assessed by the initial coronary angiography rather than by echocardiography. Coronary artery aneurysm configuration was divided into the saccular type, in which the transverse dimension is greater than half of the longitudinal dimension, and the fusiform type, including the tubular subtype, in which the transverse dimension is half of the longitudinal dimension or less.¹⁰ If multiple CAA were present in multiple arteries, the definitions were used for assessing the largest CAA and the number in the corresponding artery.

In this study, CE was defined as the presence of coronary artery thrombosis, stenosis of 75% or greater according to the American Heart Association classification, obstruction, acute ischemic events, or coronary interventions, while MACE was defined as acute ischemic events or coronary interventions. A coronary thrombosis was diagnosed by echocardiography or coronary angiography results, and stenosis and obstruction were diagnosed on the basis of the results of each coronary angiography in the follow-up interval. Acute ischemic events included unstable angina pectoris, myocardial infarction, and cardiac-related death. Coronary interventions included percutaneous transluminal coronary recanalization for coronary thrombosis, percutaneous coronary intervention (balloon dilation, stent implantation, or rotablator), and coronary artery bypass grafting. Coronary artery aneurysms were defined in accordance with the report of the Japanese Ministry of Health and Welfare¹¹ as having an actual internal diameter of 3 mm or more in a child younger than 5 years or 4 mm or more in a child 5 years or older, with the internal diameter of the segment being at least 1.5 times greater than that of an adjacent segment, or the luminal contour being clearly irregular.

Severity Classifications of CAA

The maximum coronary arterial internal diameter in each artery obtained by echocardiography, but not by coronary angiography, in the acute phase was converted to a z score using a model derived by the lambda-mu-sigma method⁷ based on data from healthy Japanese children. For the severity classification of CAA, 3 groups were formed based on 5 increments in the z score of the CAA internal diameter for the following parameters^3,4: small, z score of less than 5; medium, z score of 5 to 10 and an actual internal diameter of less than 8 mm; and large, z score of 10 or more or an actual internal diameter of 8 or more mm. Patients with an unavailable z score and an actual diameter of less than 8 mm were defined as unclassifiable. Furthermore, we evaluated the severity classification based on less than 4 mm, 4 to 6 mm, 6 to 8 mm, and 8 or more mm of the actual internal diameter by reference to the guidelines¹ of the Japanese Society of Cardiology.

Statistical Analysis

Baseline characteristics were described for all of the participants using the severity classification by median and interquartile range (IQR) for continuous variables and frequency and proportion for categorical variables. For all participants, the cumulative proportion of CE was estimated by the Kaplan-Meier method for severity classification, and comparisons were made with the log-rank test. The Cox proportional hazards regression model was used to identify factors associated with CE by calculating the hazard ratios (HRs) with a 95% confidence interval while simultaneously controlling for confounding variables, including age, sex, size, morphology, and number of CAA, and resistance to initial IVIG in the acute phase with or without use of warfarin. We also performed a similar analysis for the occurrence of MACE. A 2-sided P < .05 was considered statistically significant. All statistical analyses were carried out using SPSS, version 23.0 (IBM Corp).

Results

Patient Characteristics and Kinds of Treatments

During the study period, 1033 patients at 44 institutions received a coronary angiography. Of these patients, 27 were excluded because the echocardiographic measurements of the coronary arterial internal diameter in the acute phase were unavailable. There were no patients with other exclusion criteria, including severe disorders affecting the coronary artery lesions or prognosis. We thus enrolled 1006 patients (714 [71%] male and 292 [29%] female) in this study. The median age at KD diagnosis was 1.8 years (range, 0.07-15.7 years; IQR, 0.6-3.8 years) with a 6.4-year, median follow-up period (range, 0.04-22.5 years; IQR, 2.8-11.1 years). The first coronary angiography was performed via cardiac catheterization for all patients except 3, for whom enhanced computed tomography was performed. The patients underwent these procedures at 0.0 to 14.7 years after KD onset (median, 0.4 years; IQR, 0.2-1.4 years), and 799 patients (79%) underwent their first coronary angiography within 2 years of KD onset.

For the initial treatment, IVIG was administered to 882 of 1006 patients (88%); of these, 42 (5%) received a steroid treatment, 36 (4%) a protease inhibitor (ulinastatin or gabexate mesilate), and 3 (0.3%) infliximab in combination with IVIG. We did not obtain data on the timing of the initial IVIG administration. In total, 510 patients (58%) received additional treatment; IVIG was administered to 442 patients (50%), steroids to 209 (24%), a protease inhibitor to 112 (13%), cyclosporine to 17 (2%), infliximab to 25 (3%), and plasma exchange to 16 (2%).

Table 1 shows the patient characteristics, including the configuration and number of CAA, resistance to initial IVIG treatment, warfarin use, and the number of patients with CE and MACE by small, medium, and large CAA sizes based on the largest z score among all arteries. Coronary events and MACE did not occur in patients with small CAA, but were observed in 20 (5%) and 8 (2%) of the patients with medium CAA, and in 82 (35%) and 45 (19%) of the patients with large CAA, respectively.

Table 1. Patient Characteristics According to Classification of Coronary Artery Aneurysms.

	No. (%)
	Total	Small	Medium	Large	Unclassifiable^a
Total No. of patients	1006	134	425	273	174
Male	714 (71)	102 (76)	312 (73)	174 (64)	126 (72)
Age at diagnosis, y
<1	341 (34)	21 (16)	149 (35)	101 (37)	70 (47)
≥1-<5	501 (50)	78 (58)	225 (53)	118 (44)	80 (41)
≥5	157 (16)	35 (26)	51 (12)	52 (19)	19 (11)
Property of CAA
Configuration
Regression	630 (63)	109 (81)	273 (65)	88 (33)	160 (94)
Dilation	94 (9)	17 (13)	49 (12)	23 (9)	5 (3)
Fusiform	126 (13)	0 (0)	43 (10)	77 (29)	6 (4)
Saccular	148 (15)	8 (6)	58 (14)	82 (30)	0 (0)
No.
Single	231 (23)	19 (14)	99 (23)	79 (29)	34 (20)
Multiple	243 (24)	13 (10)	86 (20)	127 (47)	17 (10)
Treatment
Resistant to initial IVIG	510 (51)	58 (44)	214 (51)	177 (65)	61 (37)
Use of warfarin	219 (22)	1 (1)	58 (14)	149 (55)	11 (6)
Coronary imaging findings
Thrombosis	47 (5)	0 (0)	3 (1)	42 (15)	2 (1)
Stenosis	92 (9)	0 (0)	13 (3)	64 (23)	15 (9)
Obstruction	49 (5)	0 (0)	3 (1)	42 (16)	4 (2)
Ischemic heart diseases
Unstable angina	14 (1)	0 (0)	1 (0.2)	11 (4)	2 (1)
Myocardial infarction	21 (2)	0 (0)	1 (0.2)	19 (7)	1 (1)
Cardiac death	5 (0.5)	0 (0)	0 (0)	5 (2)	0 (0)
Coronary interventions
PCI	23 (2)	0 (0)	3 (1)	18 (7)	2 (1)
PTCR	28 (3)	0 (0)	2 (0.5)	25 (9)	1 (1)
CABG	20 (2)	0 (0)	1 (0.2)	18 (7)	1 (1)
End points
Coronary events^b	127 (13)	0 (0)	17 (4)	93 (34)	17 (10)
Major adverse cardiac events^c	59 (6)	0 (0)	7 (2)	50 (18)	2 (1)

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Abbreviations: CAA, coronary artery aneurysm; CABG, coronary artery bypass grafting; IVIG, intravenous immunoglobulin; PCI, percutaneous coronary intervention; PTCR, percutaneous transluminal coronary recanalization.

^{^a}

Patients with unavailable z score of the coronary arterial internal diameter and the actual diameter of less than 8 mm were defined as unclassifiable.

^{^b}

Coronary events include coronary imaging findings, ischemic heart diseases, and coronary interventions.

^{^c}

Major cardiac adverse events include ischemic heart diseases and coronary interventions.

Time-Dependent Occurrence of CE and MACE

In total, the 10-year event-free survival rate was 100%, 96%, and 61% for CE (P < .001) and 100%, 98%, and 81% for MACE (P < .001) for small, medium, and large CAA, respectively. Figure 1 shows the Kaplan-Meier curves for severity classification based on the z score of the CAA internal diameter in relation to CE in male and female patients. The 10-year event-free survival rate for CE was 100%, 94%, and 52% in male (P < .001), and 100%, 100%, and 75% in female patients (P < .001), respectively. Figure 2 shows the Kaplan-Meier curves for MACE. The 10-year event-free survival rate for MACE was 100%, 97%, and 74% in male (P < .001), and 100%, 100%, and 92% in female patients (P < .001), respectively. Similar results showing sex differences were found using the severity classification in the actual internal diameter (eFigures 1 and 2 in the Supplement).

Figure 1. — A, Coronary event–free survival rates for male patients. B, Coronary event–free survival rates for female patients. The survival curves were significantly different among the 3 groups (P < .001, log rank test of equality). Small, internal diameter z score of coronary artery aneurysms of less than 5; medium, z score of 5 to 10 and actual internal diameter of less than 8 mm; and large, z score of 10 or more or actual internal diameter of 8 mm or more.

Figure 2. — A, Major adverse cardiac event–free survival rates for male patients. B, Major adverse cardiac event–free survival rates for female patients. The survival curves were significantly different among the 3 groups (P < .001, log rank test of equality). Small, internal diameter z score of coronary artery aneurysms of less than 5; medium, z score of 5 to 10 and actual internal diameter of less than 8 mm; and large, z score of 10 or more or actual internal diameter of 8 mm or more.

Furthermore, the rate of CE was 100%, 96%, and 79% (P < .001) in patients who were not resistant to the initial IVIG treatment (P < .001) and 100%, 96%, and 51% in patients who were resistant to the initial IVIG treatment (P < .001) for small, medium, and large CAA, respectively; the rate of MACE was 100%, 97%, and 90% (P = .01) in patients who were not resistant to the initial IVIG therapy and 100%, 98%, and 76% (P < .001) in patients who were resistant to the initial IVIG therapy, respectively.

Risk Factors Associated With CE and MACE

We compared the risk of CE and MACE using the Cox proportional hazards regression model for the medium and large CAA groups because there were no events in the small CAA group. Table 2 shows the unadjusted and adjusted risk estimates for CE and MACE. In the unadjusted analysis, the statistically significant associated factors were large CAA, male sex, saccular segment morphology, multiple CAA, and resistance to initial IVIG treatment for both CE and MACE in addition to an age at diagnosis of 5 years or older for MACE. A multivariable analysis revealed that large CAA, male sex, and resistance to initial IVIG were significantly associated with an increased risk of both CE and MACE in addition to an age at diagnosis of 5 years or younger for MACE.

Table 2. Cox Regression Analysis for Coronary Events and Major Adverse Cardiac Events.

Event	Unadjusted		Adjusted
Event	Hazard Ratio (95% CI)	P Value	Hazard Ratio (95% CI)	P Value
Coronary Events
Large CAA	9.3 (5.4-15.9)	<.001	8.9 (5.1-15.4)	<.001
Male	2.4 (1.4-4.0)	.001	2.8 (1.7-4.8)	<.001
Age at diagnosis vs ≥1-<5 y
<1	0.8 (0.5-1.3)	.47	0.8 (0.5-1.3)	.45
≥5	1.4 (0.9-2.4)	.16	1.1 (0.7-1.8)	.72
Saccular CAA	2.0 (1.3-2.9)	.001	1.1 (0.7-1.7)	.61
Multiple CAA	2.6 (1.7-3.8)	<.001	1.2 (0.8-1.8)	.39
Resistant to initial IVIG	3.0 (1.9-4.9)	<.001	2.2 (1.4-3.6)	.001
Major Adverse Cardiac Events
Large CAA	12.3 (5.3-28.9)	<.001	11.5 (4.8-27.6)	<.001
Male	4.6 (1.8-11.6)	.001	5.2 (2.0-13.1)	.001
Age at diagnosis vs ≥1-<5 y
<1	1.3 (0.7-2.5)	.38	1.5 (0.8-2.9)	.21
≥5	2.6 (1.3-5.0)	.01	2.3 (1.2-4.6)	.02
Saccular CAA	2.2 (1.3-3.9)	.003	1.3 (0.7-2.2)	.41
Multiple CAA	2.5 (1.5-4.4)	.001	1.0 (0.6-1.8)	.92
Resistant to initial IVIG	4.0 (2.0-8.0)	<.001	3.1 (1.5-6.3)	.002

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Abbreviations: CAA, coronary artery aneurysm; IVIG, intravenous immunoglobulin.

When the use of warfarin was included in the explanatory variables, it was significantly associated with CE (hazard ratio [HR], 5.4; 95% CI, 3.6-8.2; P < .001) and MACE (HR, 8.1; 95% CI, 4.3-15.1; P < .001). However, the association with warfarin use was not significant if the events were confined to the thrombotic variety, including thrombosis, obstruction, percutaneous transluminal coronary recanalization, myocardial infarction, and cardiac-related death (HR, 1.4; 95% CI, 0.8-2.5; P = .32). Bilateral CAA was not significantly associated with CE or MACE in a multivariable Cox regression analysis (CE: HR, 1.9; 95% CI, 0.8-4.8; P = .18; MACE: HR, 1.6; 95% CI, 0.5-5.2; P = .47).

Discussion

This study demonstrated the use of the z score of the coronary arterial internal diameter for classifying the severity of CAA in relation to the time-dependent occurrence of CE and MACE using a large-scale cohort of more than 1000 patients with KD with CAA. While patients with KD with a large CAA had a higher risk of CE and MACE, those with a small CAA experienced no such events. It should be stressed that male sex and resistance to initial IVIG were associated with a higher occurrence of CE and MACE.

The event-free survival rate for CE and MACE was lowest for patients with a large CAA as measured by the z score of the internal diameter. Luminal myofibroblastic proliferation, as well as the layering of the mural thrombus, can reduce the internal lumen of a large CAA.¹² Together with reduced shear stress and a disturbed flow pattern,¹³ it can result in progressive coronary stenosis or even complete occlusion. On the other hand, the prognosis of patients with a small CAA may be good because the event-free survival rate was 100% for CE and MACE. However, longer-term follow-up studies are needed to define the risk of later complications.

Male sex constituted a higher risk for CE and MACE among patients with KD, suggesting that sex interacted qualitatively with the z score of the coronary arterial internal diameter. The event-free survival rate was lower among male patients and higher among female patients for medium to large CAA; notably, female patients with a medium CAA had fewer risks. We speculate that damage to the vascular wall of the coronary artery caused by inflammation in KD may be more severe in male than female patients, with resulting differences in the incidence of CE. Alternatively, the sex differences in coronary heart disease among adults could explain the sex differences seen in KD, although the contributing factors are complex and may include the role of estrogen, lifestyle, and behavior patterns.^14,15 Our findings are supported by another report¹⁶ that demonstrated that male patients, but not female patients, with cardiac sequelae due to KD had a higher mortality rate than the general population. That is to say, male patients with KD were at risk of contracting KD and developing CAA^1,17 and generally had a poorer prognosis compared with female patients.

Intravenous immunoglobulin resistance was also found to be significantly associated with both CE and MACE. We suspect that the damage to the vascular wall due to inflammation may be more severe in IVIG-resistant patients than in IVIG-nonresistant patients; consequently, more treatment-resistant patients experienced CE and MACE. Friedman et al⁸ suggested that early IVIG treatment and anti-inflammatory medications as adjuncts to IVIG within 10 days of fever onset may improve the outcome of CAA. We agree with these findings; however, we were unable to demonstrate whether the dose and timing of IVIG administration and the kinds of additional treatment affected the outcomes in our study due to confounding factors and the paucity of data.

Limitations

Our study has some limitations, mostly due to its retrospective design. First, because the timing of the angiography was not standardized across participants, data pertaining to the CAA, such as their configuration and number, may not have accurately reflected the patients’ conditions when an echocardiogram was used to measure the internal diameter. Second, patients who died before receiving an angiography were not included in this study; hence, the incidence of MACE might have been underestimated, especially in those with a large CAA. Third, the treatment protocol for the short-term and long-term cases varied at each institution. Because 2 g/kg of IVIG is not given to all patients with KD in Japan and because data on the timing of administration were not available in this study, the effect of resistance to IVIG may not have been correctly evaluated. Fourth, our findings, derived from Japanese participants, may not be applicable to other racial/ethnic groups.

Conclusions

Assessing CAA severity using the z score of the internal diameter in patients with KD was significantly related to the time-dependent occurrence of CE and MACE. Male sex and resistance to initial IVIG were significantly associated with CE and MACE. We expect that assessing the z score of the CAA internal diameter will be useful not only for preventing acute ischemic events, but also for planning new international randomized clinical trials in the future because it allows meaningful comparisons to be made among different racial/ethnic groups.¹⁸ Furthermore, other factors, including sex and IVIG resistance, should be considered in the clinical management of CAA.

Supplement.

eFigure 1. Kaplan-Meier survival curves for coronary events classified by the actual internal diameter of coronary artery aneurysms in male and female patients

eFigure 2. Kaplan-Meier survival curves for major severe cardiac events classified by the actual internal diameter of coronary artery aneurysms in male and female patients

Click here for additional data file.^{(164.2KB, pdf)}

References

1.Ogawa S, Ayusawa M, Fukazawa R, et al. ; JCS Joint Working Group . Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2013). Digest version. Circ J. 2014;78(10):-. [DOI] [PubMed] [Google Scholar]
2.Eleftheriou D, Levin M, Shingadia D, Tulloh R, Klein NJ, Brogan PA. Management of Kawasaki disease. Arch Dis Child. 2014;99(1):74-83. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Manlhiot C, Millar K, Golding F, McCrindle BW. Improved classification of coronary artery abnormalities based only on coronary artery z-scores after Kawasaki disease. Pediatr Cardiol. 2010;31(2):242-249. [DOI] [PubMed] [Google Scholar]
4.McCrindle BW, Rowley AH, Newburger JW, et al. ; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; and Council on Epidemiology and Prevention . Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135(17):e927-e999. [DOI] [PubMed] [Google Scholar]
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6.McCrindle BW, Li JS, Minich LL, et al. ; Pediatric Heart Network Investigators . Coronary artery involvement in children with Kawasaki disease: risk factors from analysis of serial normalized measurements. Circulation. 2007;116(2):174-179. [DOI] [PubMed] [Google Scholar]
7.Kobayashi T, Fuse S, Sakamoto N, et al. ; Z score Project Investigators . A new Z-Score curve of the coronary arterial internal diameter using the lambda-mu-sigma method in a pediatric population. J Am Soc Echocardiogr. 2016;29(8):794-801.e29. [DOI] [PubMed] [Google Scholar]
8.Friedman KG, Gauvreau K, Hamaoka-Okamoto A, et al. . Coronary artery aneurysms in Kawasaki disease: risk factors for progressive disease and adverse cardiac events in the US population. J Am Heart Assoc. 2016;5(9):e003289. [DOI] [PMC free article] [PubMed] [Google Scholar]
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11.Research Committee on Kawasaki Disease Report of Subcommittee on Standardization of Diagnostic Criteria and Reporting of Coronary Artery Lesions in Kawasaki Disease. Tokyo, Japan: Ministry of Health and Welfare; 1984. (in Japanese) [Google Scholar]
12.Orenstein JM, Shulman ST, Fox LM, et al. . Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic study. PLoS One. 2012;7(6):e38998. [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Ohkubo T, Fukazawa R, Ikegami E, Ogawa S. Reduced shear stress and disturbed flow may lead to coronary aneurysm and thrombus formations. Pediatr Int. 2007;49(1):1-7. [DOI] [PubMed] [Google Scholar]
14.Barrett-Connor E. Sex differences in coronary heart disease. why are women so superior? the 1995 Ancel Keys Lecture. Circulation. 1997;95(1):252-264. [DOI] [PubMed] [Google Scholar]
15.Mosca L, Barrett-Connor E, Wenger NK. Sex/gender differences in cardiovascular disease prevention: what a difference a decade makes. Circulation. 2011;124(19):2145-2154. [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Nakamura Y, Aso E, Yashiro M, et al. . Mortality among Japanese with a history of Kawasaki disease: results at the end of 2009. J Epidemiol. 2013;23(6):429-434. [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Lin MT, Sun LC, Wu ET, Wang JK, Lue HC, Wu MH. Acute and late coronary outcomes in 1073 patients with Kawasaki disease with and without intravenous γ-immunoglobulin therapy. Arch Dis Child. 2015;100(6):542-547. [DOI] [PubMed] [Google Scholar]
18.Ogata S, Tremoulet AH, Sato Y, et al. . Coronary artery outcomes among children with Kawasaki disease in the United States and Japan. Int J Cardiol. 2013;168(4):3825-3828. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eFigure 1. Kaplan-Meier survival curves for coronary events classified by the actual internal diameter of coronary artery aneurysms in male and female patients

eFigure 2. Kaplan-Meier survival curves for major severe cardiac events classified by the actual internal diameter of coronary artery aneurysms in male and female patients

Click here for additional data file.^{(164.2KB, pdf)}

[poi180002r1] 1.Ogawa S, Ayusawa M, Fukazawa R, et al. ; JCS Joint Working Group . Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2013). Digest version. Circ J. 2014;78(10):-. [DOI] [PubMed] [Google Scholar]

[poi180002r2] 2.Eleftheriou D, Levin M, Shingadia D, Tulloh R, Klein NJ, Brogan PA. Management of Kawasaki disease. Arch Dis Child. 2014;99(1):74-83. [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi180002r3] 3.Manlhiot C, Millar K, Golding F, McCrindle BW. Improved classification of coronary artery abnormalities based only on coronary artery z-scores after Kawasaki disease. Pediatr Cardiol. 2010;31(2):242-249. [DOI] [PubMed] [Google Scholar]

[poi180002r4] 4.McCrindle BW, Rowley AH, Newburger JW, et al. ; American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Surgery and Anesthesia; and Council on Epidemiology and Prevention . Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation. 2017;135(17):e927-e999. [DOI] [PubMed] [Google Scholar]

[poi180002r5] 5.de Zorzi A, Colan SD, Gauvreau K, Baker AL, Sundel RP, Newburger JW. Coronary artery dimensions may be misclassified as normal in Kawasaki disease. J Pediatr. 1998;133(2):254-258. [DOI] [PubMed] [Google Scholar]

[poi180002r6] 6.McCrindle BW, Li JS, Minich LL, et al. ; Pediatric Heart Network Investigators . Coronary artery involvement in children with Kawasaki disease: risk factors from analysis of serial normalized measurements. Circulation. 2007;116(2):174-179. [DOI] [PubMed] [Google Scholar]

[poi180002r7] 7.Kobayashi T, Fuse S, Sakamoto N, et al. ; Z score Project Investigators . A new Z-Score curve of the coronary arterial internal diameter using the lambda-mu-sigma method in a pediatric population. J Am Soc Echocardiogr. 2016;29(8):794-801.e29. [DOI] [PubMed] [Google Scholar]

[poi180002r8] 8.Friedman KG, Gauvreau K, Hamaoka-Okamoto A, et al. . Coronary artery aneurysms in Kawasaki disease: risk factors for progressive disease and adverse cardiac events in the US population. J Am Heart Assoc. 2016;5(9):e003289. [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi180002r9] 9.Saji T, Ayusawa M, Miura M, et al. ; Research Committee of the Japanese Society of Pediatric Cardiology; Cardiac Surgery Committee for Development of Guidelines for Medical Treatment of Acute Kawasaki Disease . Guidelines for medical treatment of acute Kawasaki disease: report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (2012 revised version). Pediatr Int. 2014;56(2):135-158. [DOI] [PubMed] [Google Scholar]

[poi180002r10] 10.Onouchi Z, Shimazu S, Kiyosawa N, Takamatsu T, Hamaoka K. Aneurysms of the coronary arteries in Kawasaki disease. An angiographic study of 30 cases. Circulation. 1982;66(1):6-13. [DOI] [PubMed] [Google Scholar]

[poi180002r11] 11.Research Committee on Kawasaki Disease Report of Subcommittee on Standardization of Diagnostic Criteria and Reporting of Coronary Artery Lesions in Kawasaki Disease. Tokyo, Japan: Ministry of Health and Welfare; 1984. (in Japanese) [Google Scholar]

[poi180002r12] 12.Orenstein JM, Shulman ST, Fox LM, et al. . Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic study. PLoS One. 2012;7(6):e38998. [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi180002r13] 13.Ohkubo T, Fukazawa R, Ikegami E, Ogawa S. Reduced shear stress and disturbed flow may lead to coronary aneurysm and thrombus formations. Pediatr Int. 2007;49(1):1-7. [DOI] [PubMed] [Google Scholar]

[poi180002r14] 14.Barrett-Connor E. Sex differences in coronary heart disease. why are women so superior? the 1995 Ancel Keys Lecture. Circulation. 1997;95(1):252-264. [DOI] [PubMed] [Google Scholar]

[poi180002r15] 15.Mosca L, Barrett-Connor E, Wenger NK. Sex/gender differences in cardiovascular disease prevention: what a difference a decade makes. Circulation. 2011;124(19):2145-2154. [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi180002r16] 16.Nakamura Y, Aso E, Yashiro M, et al. . Mortality among Japanese with a history of Kawasaki disease: results at the end of 2009. J Epidemiol. 2013;23(6):429-434. [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi180002r17] 17.Lin MT, Sun LC, Wu ET, Wang JK, Lue HC, Wu MH. Acute and late coronary outcomes in 1073 patients with Kawasaki disease with and without intravenous γ-immunoglobulin therapy. Arch Dis Child. 2015;100(6):542-547. [DOI] [PubMed] [Google Scholar]

[poi180002r18] 18.Ogata S, Tremoulet AH, Sato Y, et al. . Coronary artery outcomes among children with Kawasaki disease in the United States and Japan. Int J Cardiol. 2013;168(4):3825-3828. [DOI] [PMC free article] [PubMed] [Google Scholar]

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Association of Severity of Coronary Artery Aneurysms in Patients With Kawasaki Disease and Risk of Later Coronary Events

Masaru Miura, MD, PhD

Tohru Kobayashi, MD, PhD

Tetsuji Kaneko, MSc

Mamoru Ayusawa, MD, PhD

Ryuji Fukazawa, MD, PhD

Naoya Fukushima, MD

Shigeto Fuse, MD, PhD

Kenji Hamaoka, MD, PhD

Keiichi Hirono, MD, PhD

Taichi Kato, MD, PhD

Yoshihide Mitani, MD, PhD

Seiichi Sato, MD, PhD

Shinya Shimoyama, MD, PhD

Junko Shiono, MD, PhD

Kenji Suda, MD, PhD

Hiroshi Suzuki, MD, PhD

Jun Maeda, MD, PhD

Kenji Waki, MD, PhD

Hitoshi Kato, MD, PhD

Tsutomu Saji, MD, PhD

Hiroyuki Yamagishi, MD, PhD

Aya Ozeki, MSc

Masako Tomotsune, BN

Makiko Yoshida, BPhrm

Yohei Akazawa, MD, PhD

Kentaro Aso, MD, PhD

Shouzaburoh Doi, MD, PhD

Yoshi Fukasawa, MD

Kenji Furuno, MD, PhD

Yasunobu Hayabuchi, MD, PhD

Miyuki Hayashi, MD, PhD

Takafumi Honda, MD

Norihisa Horita, MD, PhD

Kazuyuki Ikeda, MD, PhD

Masahiro Ishii, MD, PhD

Satoru Iwashima, MD, PhD

Masahiro Kamada, MD, PhD

Masahide Kaneko, MD

Hiroshi Katyama, MD, PhD

Yoichi Kawamura, MD, PhD

Atushi Kitagawa, MD, PhD

Akiko Komori, MD

Kenji Kuraishi, MD

Hiroshi Masuda, MD

Shinichi Matsuda, MD

Satoshi Matsuzaki, MD, PhD

Sayaka Mii, MD

Tomoyuki Miyamoto, MD

Yuji Moritou, MD

Noriko Motoki, MD, PhD

Kiyoshi Nagumo, MD, PhD

Tsuneyuki Nakamura, MD

Eiki Nishihara, MD

Yuichi Nomura, MD, PhD

Shohei Ogata, MD, PhD

Hiroyuki Ohashi, MD

Kenichi Okumura, MD, PhD

Daisuke Omori, MD

Tetsuya Sano, MD

Eisuke Suganuma, MD, PhD

Tsutomu Takahashi, MD, PhD

Shinichi Takatsuki, MD

Atsuhito Takeda, MD, PhD

Masaru Terai, MD, PhD

Manatomo Toyono, MD, PhD

Kenichi Watanabe, MD, PhD

Makoto Watanabe, MD

Masaki Yamamoto, MD

Kenichiro Yamamura, MD, PhD

Key Points

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Abstract

Importance

Objective

Design, Setting, and Participants

Main Outcomes and Measures