Abstract
Heart disease is a major global threat. Triglyceride deposit cardiomyovasculopathy (TGCV) is an emerging, noncommunicable, adult-onset heart disease, first identified in Japanese patients with heart failure (HF) requiring cardiac transplantation1,2,3. In TGCV, defective intracellular lipolysis of long-chain triglycerides (TGs) results in cellular steatosis and energy failure mainly in cardiomyocytes4 and smooth muscle cells5, leading to HF, diffuse coronary artery disease with TG deposition and ventricular arrhythmias with high mortality6. Tricaprin, a class of medium-chain TGs, recently corrected myocardial TG lipolysis7. Here we report remarkable long-term survival and durable recovery of HF in patients with TGCV treated with supplemental tricaprin in registry studies. Our study offers a classification of heart disease caused by defective lipolysis and its possible practical treatment. Because myocardial lipid droplets are a common feature in HF and their potential as therapeutic targets has been discussed worldwide, our findings warrant investigation into other ethnicities.
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Data availability
Under compliance with the Act on the Protection of Personal Information in Japan, any data presented in this paper are available upon reasonable request to the corresponding author (khirano@cnt-osaka.com). A response will be provided within 6 months after the initial request. Use of the data will be permitted only for scientific and academic research purposes, citing that the data is from this paper.
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Acknowledgements
We thank S. Tarui (Osaka University), M. Hori (Osaka University), D. Nakatani (Osaka University), T. Aoyama (Kyoto Koka Women’s University), T. Ide (Kyushu University) and M. Fukushima (Kyoto University.) for their continuous encouragement since the initiation of the study. We thank S. Oshima (Nagoya Kyoritsu Hospital), Y. Tokumasu (Shizuoka City Shizuoka Hospital), K. Shimada (Senkawadori Clinic), I. Kurihara (KKR Tohoku Kosai Hospital), K. Yanagihara (Saiseikai Sakaiminato Hospital), T. Okumura (Nagoya University), S. Tadaki (Kesennuma City Hospital) and K. Yamamoto (Tottori University) for taking care of the patients and providing their clinical data. We thank B. Zhang (Fukuoka University) for statistical advice. We thank N. Ikeda (The Nisshin OilliO Group) and S. Watanabe (The Nisshin OilliO Group) for donating their products to the TGCV/NLSD Patient Association. This study was partially supported by research grants for rare diseases from the Ministry of Health, Labour, and Welfare (no. 24FC1007) and the Japan Agency of Medical Research and Development (no. 22ek0109479h003) to K.H. This study was also supported by Nihon Medi-Physics in the form of donated supplies to K.H.
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Authors and Affiliations
Contributions
K.H. conceptualized the study, acquired the funding, investigated and analyzed the data, and wrote the original manuscript. S.O. contributed to the formal analyses of registry data and data visualization, and wrote parts of the original manuscript. K.S., K. Nochioka, Y. Nakano, M.H., S.S., H.S., S.F. and Y.S. contributed to the investigation and resources, and edited and reviewed the manuscript. H.M. and Y. Nakano wrote the original manuscript and provided scientific discussions. C.H. managed the project and was the representative caretaker for the Patient Association. Y. Iwanaga and M.O. performed the formal analyses and visualization of cardiac imaging. K. Nakajima performed the formal analyses and visualization of nuclear imaging. S.Y., S.P.H. and N.Z. performed the formal analyses of lipids, and edited and reviewed the manuscript. Y.Y. conceptualized and provided support for the tricaprin therapy. Y. Nishimura managed the project and validated the registry. Y. Nagasawa, T.A., T.Y. and K.K. supervised their respective specialties and assisted in writing, reviewing and editing the manuscript. Y. Ikeda and S.K. performed the formal analyses and visualization of the pathological specimens. K.H. accessed and verified the data. No authors were precluded from accessing the study data. All authors viewed and approved the final report.
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Competing interests
K.H. has been a Joint Research Chair in collaboration with Toa Eiyo since February 2021 and has served as a medical adviser for Toa Eiyo since December 2021. K.H. has two granted (PCT/JP2012/071594 and PCT/JP2021/008689) and one patent pending (PCT/JP2021/025687). K.H. reports lecture fees from Nihon Medi-Physics. K.H. is the president (unpaid) of the Tochino Foundation and the Society of Triglyceride Biology and Medicine (TGBM). K.S. reports lecture fees from Bayer Yakuhin, Janssen Pharmaceutical, Novartis Pharma and Otsuka Pharmaceutical. H.M. has a patent granted (PCT/JP2023/032407) and is a director (unpaid) of TGBM. H.M. reports lecture fees from Nihon Medi-Physics and Toa Eiyo. Y. Nakano reports a grant from the Japan Society for the Promotion of Science outside the submitted work and lecture fees from Otsuka Pharma, Kowa, Astellas Pharma, AstraZeneca, Daiichi Sankyo and Ono Pharmaceutical. C.H. is a representative caretaker (unpaid) of the TGCV/NLSD Patient Association, a director (unpaid) of TGBM and an employee of the Tochino Foundation. K. Nakajima receives funds for the endowed department (Functional Imaging and Artificial Intelligence, Kanazawa University) from Siemens Healthcare Japan, Nihon Medi-Physics (Japan) and PDRadiopharma (Japan); he has collaborated with Spectrum Dynamics Medical (Israel). S.Y. reports research grants from Nihon Medi-Physics and the Kowa Health Science Council. S.Y. is a representative director (unpaid) of Triglyceride Laboratory and Business and a managing director (paid) of the Tochino Foundation, which paid joint research fees to Osaka University. Y.Y. is a nutritional adviser (unpaid) for the TGCV/NLSD Patient Association. Y.Y., N.Z. and Y. Ikeda have a patent granted (PCT/JP2012/071594). M.H. reports a Takeda Research Grant outside the submitted work and lecture fees from Sumitomo, Novartis, Ono, Kyowa-Kirin, Takeda, Eisai, Otsuka and Chugai. T.A. reports lecture fees from Astellas Pharma, AstraZeneca, Bayer, Daiichi Sankyo and Bristol Myers Squibb. S.F. reports lecture fees from Nihon Medi-Physics and Toa Eiyo Ltd. Y.S. reports collaborative research with TOSHIBA., Fuji Yakuhin and FornesLife, and speaker/lecture fees from AstraZeneca, Ono Pharmaceutical, Eli Lilly, Kowa Pharmaceutical and Nippon Boehringer Ingelheim outside the submitted work. K.K. is a director (unpaid) of TGBM. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Milestones of research and development of tricaprin treatment for TGCV.
In 2006, we began the initial studies (pink box) to develop a specific therapy for a patient with primary TGCV waiting for cardiac transplantation (data shown in Extended Data Fig. 2), which raised a therapeutic hypothesis that tricaprin improves defective intracellular lipolysis in TGCV. Considering the rarity and potentially severe life-threatening prognosis of TGCV, and the status of the health-care system including the absolute deficiency of donor hearts for CTx and availability of research funds for rare diseases in Japan, we decided to simultaneously commit to the following two programmes: 1) investigator-initiated development of the first-in-class orphan drug, CNT-01 (with the active ingredient tricaprin) for TGCV, supported by governmental rare disease grants and 2) the compassionate practical programme for symptomatic patients, particularly those resistant to standard medical therapies and interventions, in which patients received supplemental tricaprin in collaboration with the TGCV/NLSD Patient Association. We describe the latter in the present paper (green box in the figure above). Abbreviations: CTx, cardiac transplantation; NLSD, neutral lipid storage disease with myopathy; TGCV, triglyceride deposit cardiomyovasculopathy.
Extended Data Fig. 2 In vitro and in vivo data from initial studies (A and B) and a raised therapeutic hypothesis (C).
A. Skin fibroblasts obtained from a patient with P-TGCV carrying homozygous PNPLA2 mutation (c.696+1G>C)2 were cultured for 48 h in a medium containing 500 μM of several kinds of fatty acids conjugated with bovine serum albumin (BSA). Treatment with capric acid (C10:0) reduces cellular TG contents. Data are expressed as relative TG contents compared with those with control (BSA only) (log2-fold change). Error bars indicate standard error. Following two-sided Student’s t-test between control and each fatty acid, adjusted p-values were calculated using multiple comparison method of Bonferroni. B. This patient received 50-day dietary therapy containing 9.0 g of tricaprin before CTx. Improved RQ and fat oxidation were observed using indirect calorimetry (Aeromonitor AE-300S, Minato Medical Science, Osaka, Japan). Enzymatically measured myocardial TG content was markedly reduced in myocardial specimens obtained from CTx, compared with that obtained before the initiation of tricaprin intake. Error bars indicate standard deviation. P-values were calculated using two-sided Student’s t-test. This study was approved by the Ethics Review Committee of Osaka University Hospital (No. 07148). C. The left panel shows extracellular (plasma) and intracellular metabolism of TG in normal conditions. Several intracellular TG lipases and enzymes hydrolyse TG to supply LCFA for mitochondrial oxidation. In TGCV (middle panel), intracellular TG hydrolysis is defective, leading to TG deposition and energy failure in affected cells. Tricaprin (right panel) may facilitate intracellular TG lipolysis independent of ATGL. Abbreviations: ATGL, adipose triglyceride lipase; CTx, cardiac transplantation; DG, diacylglycerol; HSL, hormone-sensitive lipase; LCFA, long-chain fatty acid; LPL, lipoprotein lipase; MG, monoacylglycerol; MGL, monoacylglycerol lipase; RQ, respiratory quotient; TG, triglyceride; P-TGCV, primary triglyceride deposit cardiomyovasculopathy.
Extended Data Fig. 3 Patient registration and analytical flow.
A total of 212 patients with a definite diagnosis of TGCV was registered. Among them, 22 patients received tricaprin treatment. The remaining 190 patients without tricaprin treatment were served as controls for survival analyses. The overall survival rates were also analyzed in patients with heart failure. *Matching method was described in the main text. Abbreviations: NYHA, New York Heart Association Class; TGCV, triglyceride deposit cardiomyovasculopathy.
Extended Data Fig. 4 Kaplan-Meier curves with the 61-days landmark analysis in tricaprin and control groups.
The difference of overall survival between tricaprin and control groups became smaller, which was not large enough to affect our main conclusion.
Extended Data Fig. 5 Clinicopathological findings in Case 4.
A. Before tricaprin treatment, chest radiography (left) and CMR (middle and right) showed cardiomegaly with 9% of left ventricular ejection fraction. The very thin posterolateral wall was positive for LGE. Endomyocardial biopsy showed massive cardiomyocyte steatosis (data not shown), as previously reported22. B. Tricaprin increased the washout rate of 123I-β-methyl-p-iodophenyl-pentadecanoic acid in both the heart and liver in planar images. C. Comparison of macroscopic (upper and middle) and microscopic (lower) myocardial appearance of autopsied hearts between case 4 (middle) and two controls: a normal heart from an 80-year-old man who died from non-heart-related disease (left) and the heart from a 24-year-old man with primary TGCV (right), not treated with tricaprin40. In case 4 (middle panels), epicardial and myocardial lipid deposition was much milder than that in a TGCV patient without tricaprin treatment, which showed a whitish and yellowish myocardium with numerous cardiomyocytes displaying vacuolar degeneration with a vesicular appearance in haematoxylin and eosin staining (right panels). Scale bars in the upper, middle, and lower columns are 2 cm, 1 cm, and 20 μm, respectively. D. Macroscopic appearance of transverse sections of the autopsied heart. Gross image (left) and Masson’s trichrome staining (right) are shown. Severe fibrosis was observed in the posterolateral walls, corresponding to the CMR images obtained before tricaprin treatment was initiated (right, Panel A). Abbreviations: CMR, cardiac magnetic resonance; LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; P-TGCV, primary triglyceride deposit cardiomyovasculopathy.
Extended Data Fig. 6 A Hypothetical model of the detailed mechanism of action of tricaprin.
Capric acid (C10:0) is incorporated into the TG pool to form chimeric TG with long-chain fatty acid. The existence of such chimeric TG was determined by Orbitrap light chromatography mass spectrometry (data not shown). TG with C10:0 is preferentially hydrolysed by enzymes (that is carboxy-esterase) possessing lipolytic activities other than ATGL12. Abbreviations: ATGL, adipose triglyceride lipase; C10:0, capric acid; LCFA, long-chain fatty acid; TG, triglyceride; TGCV, triglyceride deposit cardiomyovasculopathy.
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Source Data Extended Data Tables 1 and 3. Source Data Fig. 1
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Source Data Fig. 2
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Source Data Fig. 3
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Source Data Extended Data Fig. 2
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Hirano, Ki., Okamura, S., Sugimura, K. et al. Long-term survival and durable recovery of heart failure in patients with triglyceride deposit cardiomyovasculopathy treated with tricaprin. Nat Cardiovasc Res 4, 266–274 (2025). https://doi.org/10.1038/s44161-025-00611-7
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DOI: https://doi.org/10.1038/s44161-025-00611-7
