Tribute to Dr. Tomomi Ide, MD, PhD

We lost a valuable ‘next generation’ leader of cardiovascular medicine in Japan with the passing of Dr. Tomomi Ide. She passed away on May 17, 2024, at the age of 54, after a long battle with cancer.

Dr. Ide graduated from Kyushu University School of Medicine in 1995. After training in clinical practice and research under Professor Akira Takeshita, she became Assistant Professor in the Department of Cardiovascular Medicine at Kyushu University Hospital in 2008, Lecturer in 2011, and Associate Professor of Cardiovascular Medicine, Faculty of Medicine, in 2017. She performed basic research as a postdoctoral research fellow at the University of Pennsylvania from 2001 to 2003.

Dr. Ide conducted basic and clinical research, mainly on heart failure, over 25 years. She focused on oxidative stress in myocardial remodeling and failure and, in particular, the role of mitochondria as its source.^1–8 She promoted her basic and translational research widely by collaborating with Japanese and international research groups from academia and industries. In recent years, she demonstrated that ferroptosis, caused by excess iron and lipid peroxides, could play an important role in the pathogenesis of cardiomyopathy and myocardial ischemia repefusion injury.^9–12 Her research group showed that doxorubicin accumulated in mitochondria by intercalating into mitochondrial DNA (mtDNA), inducing ferroptosis in an mtDNA content-dependent manner. In addition, doxorubicin disrupted heme synthesis by decreasing the abundance of 5’-aminolevulinate synthase 1 (Alas1), the rate-limiting enzyme in this process, thereby impairing iron utilization, resulting in iron overload and ferroptosis in mitochondria in cardiac myocytes. Administration of 5-aminolevulinic acid (5-ALA), the product of Alas1, to cardiac myocytes and mice suppressed iron overload and lipid peroxidation, thereby preventing doxorubicin-induced ferroptosis and cardiomyopathy. These findings support the novel concept that the accumulation of doxorubicin and iron in mitochondria cooperatively induces ferroptosis in cardiac myocytes and suggest that 5-ALA can be a potential therapeutic agent for doxorubicin-induced cardiomyopathy.

As for clinical research, Dr. Ide established a contemporary nationwide registry database for heart failure patients in Japan (Japanese Registry Of Acute Decompensated Heart Failure [JROADHF] and JROADHF-NEXT). JROADHF revealed that hospitalized heart failure patients were very elderly, that heart failure with preserved ejection fraction (HFpEF) was common, and that in Japan their prognosis was still poor.¹³ This study provided the clinical characteristics of heart failure patients for ‘real-world’ clinical practice in Japan,^13–16 and also the efficacy of pharmacological and non-pharmacological treatments such as cardiac rehabilitation and ablation for atrial fibrillation.^17,18

In recent years, Dr. Ide and her colleagues performed clinical research by incorporating modern technologies such as artificial intelligence (AI), including machine learning and deep learning, and information communication technology (ICT). She used AI to enhance diagnostic and prognostic capabilities in patients with cardiovascular diseases by utilizing big data such as patient registry databases and electrocardiograms (ECG). Machine learning-based prognostic prediction models were developed from the administrative claim data on 10,175 heart failure patients from JROADHF.¹⁹ Importantly, administrative claim data are in a structured database and suitable for machine learning analysis. This machine learning model, based only on administrative claim data but without any clinical record data, could predict the 1-year mortality of heart failure patients with high accuracy and achieve superior performance compared with that of conventional risk models. The easy operability of this approach has clear merit, even by non-healthcare providers, with a user-friendly online interface, and risk models developed using machine learning can provide a novel modality for risk stratification of patients with heart failure. Dr. Ide’s AI research team also developed a deep learning model using preoperative ECG, which can be an effective screening tool for identifying high-risk patients with postoperative atrial fibrillation who will require appropriate ECG monitoring during the postoperative period.²⁰ They also used deep-learning approaches to identify anaerobic threshold (AT) in real time during cardiopulmonary exercise testing and to predict peak oxygen uptake (peak V̇O₂) at real-time AT.²¹ AI models for real-time cardiopulmonary exercise testing analysis could accurately identify AT and predict peak V̇O₂. It can be a competent assistant system to assess a patient’s condition in real time, expanding the easier use of cardiopulmonary exercise testing in daily clinical practice. These finding are of great clinical importance because exercise intolerance is a clinical feature of patients with heart failure and cardiopulmonary exercise testing is the first-line examination for assessing exercise capacity in heart failure. Nevertheless, the use of cardiopulmonary exercise testing is limited due to the need for extensive experience in assessing AT and the potential risk associated with an excessive exercise load when measuring peak V̇O₂.

Dr. Ide and physical therapists working with her at Kyushu University Hospital developed a comprehensive home-based cardiac rehabilitation program that combined patient education, exercise guidance, and nutritional guidance using ICT.²² They showed that it could improve lower extremity muscle strength and exercise tolerance in patients with heart failure and physical frailty, suggesting that management with an individualized ICT-based program is a safe and effective approach. Considering the increasing number of heart failure patients with frailty worldwide, their approach provides an efficient method to keep patients engaged in physical activity in their daily life. Dr. Ide authored and co-authored more than 200 publications and has been recognized as an outstanding ‘physician scientist’ in the field of cardiovascular medicine not only in Japan but also globally.

Poster session during the American Heart Association Scientific Conference on Molecular Mechanisms of Growth, Death and Regeneration in the Myocardium in Snowbird, Utah, August 13–17, 2003.

Dr. Ide provided cardiovascular care, which included patients with heart failure and cardiomyopathy at Kyushu University Hospital. In particular, since 2003, she managed a number of severe heart failure patients with a ventricular assist device waiting for heart transplant and established a multidisciplinary team, including physical therapists, nurses, pharmacists, and a dietician, to perform cardiac rehabilitation. Dr. Ide was also highly involved in teaching medical students, residents, master and PhD course students, and cardiology fellows through lectures and bedside teaching in cardiology wards, and was seen to be a valued friend as well as a trusted supervisor.

Dr. Ide was active on various committees for the Japanese Circulation Society, the Japanese Heart Failure Society, the International Society for Heart Research, the Japanese Association of Cardiac Rehabilitation, and the Japanese Onco-Cardiology Society. This included serving on the boards of the Next Generation Committee, The Basic Law/Five-Year Plan Committee, Scientific Committee, JCS-JJC Committee, and Guideline Committee of the Japanese Circulation Society starting from 2016. She also served as an Associate Editor of Circulation Reports since 2019. She contributed to ‘Cardiomyopathy Treatment Guidelines 2018’ and ‘2021 JCS/JHFS Acute and Chronic Heart Failure Treatment Guidelines Focus Update’.^23,24

Despite her difficult health conditions, Dr. Ide remained energetic and optimistic, and continued to contribute to clinical practice, research, and education for as long as she could. She is survived by her family, her husband, and two children. She will also be remembered by all of the people who worked with her. We will never forget Dr. Tomomi Ide always smiling, she will live on in our hearts forever.

Disclosures

None.

References

• 1.   Ide T, Tsutsui H, Kinugawa S, Utsumi H, Kang D, Hattori N, et al. Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res 1999; 85: 357–363.
• 2.   Ide T, Tsutsui H, Kinugawa S, Utsumi H, Takeshita A. Amiodarone protects cardiac myocytes against oxidative injury by its free radical scavenging action. Circulation 1999; 100: 690–692.
• 3.   Ide T, Tsutsui H, Kinugawa S, Suematsu N, Hayashidani S, Ichikawa K, et al. Direct evidence for increased hydroxyl radicals originating from superoxide in the failing myocardium. Circ Res 2000; 86: 152–157.
• 4.   Ide T, Tsutsui H, Hayashidani S, Kang D, Suematsu N, Nakamura K, et al. Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ Res 2001; 88: 529–535.
• 5.   Ide T, Tsutsui H, Ohashi N, Hayashidani S, Suematsu N, Tsuchihashi M, et al. Greater oxidative stress in healthy young men compared with premenopausal women. Arterioscler Thromb Vasc Biol 2002; 22: 438–442.
• 6.   Tsutsui H, Ide T, Hayashidani S, Suematsu N, Shiomi T, Wen J, et al. Enhanced generation of reactive oxygen species in the limb skeletal muscles from a murine infarct model of heart failure. Circulation 2001; 104: 134–136.
• 7.   Tsutsui H, Ide T, Shiomi T, Kang D, Hayashidani S, Suematsu N, et al. 8-oxo-dGTPase, which prevents oxidative stress-induced DNA damage, increases in the mitochondria from failing hearts. Circulation 2001; 104: 2883–2885.
• 8.   Matsushima S, Ide T, Yamato M, Matsusaka H, Hattori F, Ikeuchi M, et al. Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice. Circulation 2006; 113: 1779–1786.
• 9.   Tadokoro T, Ikeda M, Ide T, Deguchi H, Ikeda S, Okabe K, et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight 2020; 5: e132747.
• 10.   Abe K, Ikeda M, Ide T, Tadokoro T, Miyamoto HD, Furusawa S, et al. Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis. Sci Signal 2022; 15: eabn8017.
• 11.   Miyamoto HD, Ikeda M, Ide T, Tadokoro T, Furusawa S, Abe K, et al. Iron overload via heme degradation in the endoplasmic reticulum triggers ferroptosis in myocardial ischemia-reperfusion injury. JACC Basic Transl Sci 2022; 7: 800–819.
• 12.   Ishimaru K, Ikeda M, Miyamoto HD, Furusawa S, Abe K, Watanabe M, et al. Deferasirox targeting ferroptosis synergistically ameliorates myocardial ischemia reperfusion injury in conjunction with cyclosporine A. J Am Heart Assoc 2024; 13: e031219.
• 13.   Ide T, Kaku H, Matsushima S, Tohyama T, Enzan N, Funakoshi K, et al; JROADHF Investigators. Clinical characteristics and outcomes of hospitalized patients with heart failure from the large-scale Japanese Registry Of Acute Decompensated Heart Failure (JROADHF). Circ J 2021; 85: 1438–1450.
• 14.   Horiuchi Y, Asami M, Ide T, Yahagi K, Komiyama K, Yuzawa H, et al. Prevalence, characteristics and cardiovascular and non-cardiovascular outcomes in patients with heart failure with supra-normal ejection fraction: Insight from the JROADHF study. Eur J Heart Fail 2023; 25: 989–998.
• 15.   Nagata T, Ide T, Tohyama T, Kaku H, Enzan N, Matsushima S, et al. Long-term outcomes of heart failure patients with preserved, mildly reduced, and reduced ejection fraction. JACC Asia 2023; 3: 315–316.
• 16.   Hamatani Y, Enzan N, Iguchi M, Yoshizawa T, Kawaji T, Ide T, et al. Atrial fibrillation type and long-term clinical outcomes in hospitalized patients with heart failure: Insight from JROADHF. Eur Heart J Qual Care Clin Outcomes 2024; 10: 193–202.
• 17.   Enzan N, Matsushima S, Kaku H, Tohyama T, Nezu T, Higuchi T, et al. Propensity-matched study of early cardiac rehabilitation in patients with acute decompensated heart failure. Circ Heart Fail 2023; 16: e010320.
• 18.   Sakamoto K, Tohyama T, Ide T, Mukai Y, Enzan N, Nagata T, et al. Efficacy of early catheter ablation for atrial fibrillation after admission for heart failure. JACC Clin Electrophysiol 2023; 9: 1948–1959.
• 19.   Tohyama T, Ide T, Ikeda M, Kaku H, Enzan N, Matsushima S, et al. Machine learning-based model for predicting 1 year mortality of hospitalized patients with heart failure. ESC Heart Fail 2021; 8: 4077–4085, doi:10.1002/ehf2.13556.
• 20.   Tohyama T, Ide T, Ikeda M, Nagata T, Tagawa K, Hirose M, et al. Deep learning of ECG for the prediction of postoperative atrial fibrillation. Circ Arrhythm Electrophysiol 2023; 16: e011579.
• 21.   Watanabe T, Tohyama T, Ikeda M, Fujino T, Hashimoto T, Matsushima S, et al. Development of deep-learning models for real-time anaerobic threshold and peak VO2 prediction during cardiopulmonary exercise testing. Eur J Prev Cardiol 2024; 31: 448–457.
• 22.   Nagatomi Y, Ide T, Higuchi T, Nezu T, Fujino T, Tohyama T, et al. Home-based cardiac rehabilitation using information and communication technology for heart failure patients with frailty. ESC Heart Fail 2022; 9: 2407–2418.
• 23.   Tsutsui H, Ide T, Ito H, Kihara Y, Kinugawa K, Kinugawa S, et al. JCS/JHFS 2021 guideline focused update on diagnosis and treatment of acute and chronic heart failure. J Card Fail 2021; 27: 1404–1444.
• 24.   Kitaoka H, Tsutsui H, Kubo T, Ide T, Chikamori T, Fukuda K, et al; Japanese Circulation Society Joint Working Group. JCS/JHFS 2018 guideline on the diagnosis and treatment of cardiomyopathies. Circ J 2021; 85: 1590–1689.